Chemical compounds

ABSTRACT

Provided are a series of novel pyridine or pyrimidine derivatives which inhibit CDK9 and may be useful for the treatment of hyperproliferative diseases. In particular the compounds are of use in the treatment of proliferative disease such as cancer including hematological malignancies such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt&#39;s lymphoma, follicular lymphoma and solid tumors such as breast cancer, lung cancer, neuroblastoma and colon cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 15/193,826,filed Jun. 27, 2016, which claims priority to provisional applicationNo. 62/185,852, filed Jun. 29, 2015, each of which is incorporated byreference in its entirety.

The present invention relates to certain pyridine or pyrimidinederivatives for use in the treatment of certain diseases in particularto proliferative disease such as cancer and in the preparation ofmedicaments for use in the treatment of proliferative disease, to novelpyridine or pyrimidine derivatives and to processes for theirpreparation, as well as pharmaceutical compositions containing them asactive ingredient.

Cyclin-dependent protein kinases (CDKs) represent a family ofserine/threonine protein kinases that become active upon binding to acyclin regulatory partner. CDK/cyclin complexes were first identified asregulators of cell cycle progression. More recently however, CDK/cyclincomplexes have also been implicated in transcription and mRNAprocessing. CDK9/PTEFb (positive transcription elongation factor b)phosphorylates the carboxyl-terminal domain (CTD) of the large subunitof RNA polymerase II (RNAP II), predominantly Ser-2, regulatingelongation of transcription. Inhibition of CDK9 and transcriptionalrepression results in the rapid depletion of short lived mRNAtranscripts and associated proteins including Mc11 and c-myc, leading toinduction of apoptosis in tumor cells hyper dependent on these survivalproteins. Targeting transcriptional CDKs including CDK9, therefore,represents a therapeutic strategy for treating tumor types hyperdependent on these labile pro-survival proteins including, but notlimited to, hematological malignancies such as acute myeloid leukemia,multiple myeloma, chronic lymphocytic leukemia, diffuse large B celllymphoma, Burkitt's lymphoma, follicular lymphoma and solid tumors suchas breast cancer, lung cancer, neuroblastoma and colon cancer. CDK9inhibitors may also have therapeutic utility in other diseaseindications including cardiology, virology, inflammation and pain.

Disclosed herein are a series of novel pyridine or pyrimidinederivatives which inhibit CDK9 and may be useful for the treatment ofhyperproliferative diseases. In particular the compounds are of use inthe treatment of proliferative disease such as cancer includinghematological malignancies such as acute myeloid leukemia, multiplemyeloma, chronic lymphocytic leukemia, diffuse large B cell lymphoma,Burkitt's lymphoma, follicular lymphoma and solid tumors such as breastcancer, lung cancer, neuroblastoma and colon cancer.

FIG. 1 is a representative X-ray powder diffractogram of Form A of(1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(Example 14).

FIG. 2 is a representative DSC/TGA thermograph of Form A of(1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(Example 14).

FIG. 3 is a representative X-ray powder diffractogram of Form A of(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide(Example 25).

FIG. 4 is a representative DSC/TGA thermograph of Form A of(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide(Example 25).

FIG. 5 is a representative X-Ray powder diffractogram of Form B of(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide(Example 86).

FIG. 6 is a representative DSC/TGA thermograph of Form B of(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide(Example 86).

FIG. 7 is a representative X-ray powder diffractogram of Form B of(1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(Example 2).

FIG. 8 is a representative DSC/TGA thermogram of Form B of(1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(Example 2).

DESCRIPTION OF THE INVENTION

According to one aspect of the present invention is provided compoundsof Formula I:

wherein:

A is C(R⁵) or N;

R⁵ is H, C₁₋₃ alkyl, CN or halogen;

R² is 3-7 membered heterocycloalkyl or 3-7 membered cycloalkyl;optionally substituted with one to three substituents independentlyselected from the group consisting of R¹⁰, OR¹⁰, SR¹⁰, S(O)R¹⁰,S(O)₂R¹⁰, C(O)R¹⁰, C(O)OR¹⁰, OC(O)R¹⁰, OC(O)OR¹⁰, NH₂, NHR¹⁰, N(R¹⁰)₂,NHC(O)H, NHC(O)R¹⁰, NR¹⁰C(O)H, NR¹⁰C(O)R¹⁰, NHS(O)₂R¹⁰, NR¹⁰S(O)₂R¹⁰,NHC(O)OR¹⁰, NR¹⁰C(O)OR¹⁰, NHC(O)NH₂, NHC(O)NHR¹⁰, NHC(O)N(R¹⁰)₂,NR¹⁰C(O)NH₂, NR¹⁰C(O)NHR¹⁰, NR¹⁰C(O)N(R¹⁰)₂, C(O)NH₂, C(O)NHR¹⁰,C(O)N(R¹⁰)₂, C(O)NHOH, C(O)NHOR¹⁰, C(O)NHS(O)₂R¹⁰, C(O)NR¹⁰S(O)₂R¹⁰,S(O)₂NH₂, S(O)₂NHR¹⁰, S(O)₂N(R¹⁰)₂, S(O)₂NHC(O)OR¹⁰, S(O)₂NR¹⁰C(O)OR¹⁰,C(O)H, C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein one or more ringCH₂ groups can optionally be replaced by a corresponding number of —C(O)groups, one or more ring sulfur or nitrogen atoms may be optionallyoxidized to form S-oxides or N-oxides;

R¹⁰, at each occurrence, is independently selected from the groupconsisting of a 3 to 6 membered cycloalkyl or heterocycloalkyl group,C₁₋₆ alkyl, —O—C₁₋₆ alkyl, C₁₋₆ alkyl-O—C₁₋₆ alkyl, NH₂, C(O)NH₂, C(O)H,C(O)OH, OH, CN, NO₂, F, Cl, Br and I; wherein two R¹⁰ groups togetherwith the atoms to which they are attached may form a 3 to 6 memberedcycloalkyl or heterocycloalkyl group; and each aforementioned R¹⁰ alkyl,cycloalkyl and heterocycloalkyl group may be further substituted withone or two substituents independently selected from CN, OH, halogen,C₁₋₃ alkyl, —O—C₁₋₃ alkyl, NH₂, NH—C₁₋₃ alkyl, and NHC(O)—C₁₋₃ alkyl.

R⁴ is

wherein X and Y together with the atoms to which they are attached, forma 5 to 7 membered heterocycloalkyl ring which, in addition to the bridgenitrogen, may contain one or two heteroatoms selected from N, O, and Swhich ring may be saturated or partially saturated; wherein one or tworing CH₂ groups can optionally be replaced by a corresponding number of—C(O) groups, one or more ring sulfur or nitrogen atoms which may beoptionally oxidized to form S-oxides or N-oxides and wherein the ringmay be substituted on a ring carbon by one or two R¹⁰ substituents or ona ring nitrogen by an R¹² substituent;

J is N or CR¹¹;

R¹¹ is H, C₁₋₃ alkyl; and

R¹² is at each occurrence independently selected from the groupconsisting of a 3 to 6 membered cycloalkyl or heterocycloalkyl group,C₁₋₆ alkyl, C₁₋₆ alkyl-O—C₁₋₆ alkyl, C(O)NH₂, C(O)H; wherein R¹² alkyl,cycloalkyl and heterocycloalkyl group may be further substituted withone or two substituents independently selected from CN, OH, and halogen,C₁₋₃ alkyl, NH₂, and NH—C₁₋₃ alkyl, NHC(O)—C₁₋₃ alkyl, or pharmaceuticalacceptable salts thereof.

Compounds of Formula (I) are useful for their ability to inhibit CDK9activity and are accordingly also useful in the treatment of diseases ormedical conditions mediated alone or in part by CDK9.

Compounds of Formula (I) may be useful for the treatment ofhyperproliferative diseases. In particular the compounds are of use inthe treatment of proliferative disease such as cancer, includinghematological malignancies such as, but not limited to acute myeloidleukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse largeB cell lymphoma, Burkitt's lymphoma, follicular lymphoma and solidtumors such as, but not limited to, breast cancer, lung cancer(including but not limited to non-small cell lung cancer (NSCLC))including the non-squamous and squamous subtypes, neuroblastoma andcolon cancer.

The invention also relates to processes for the manufacture of saidcompounds, to pharmaceutical compositions containing them, and to theiruse in the manufacture of medicaments for use in the production of ananti-proliferation effect in warm-blooded animals such as man. Also inaccordance with the present invention there are provided methods ofusing said compounds or pharmaceutically acceptable salts thereof in thetreatment of cancer.

In order that the present invention can be more readily understood,certain terms are first defined. Additional definitions are set forththroughout the detailed description.

The foregoing written specification is considered to be sufficient toenable one skilled in the art to practice the embodiments. The foregoingdescription and Examples detail certain embodiments and describes thebest mode contemplated by the inventors. It will be appreciated,however, that no matter how detailed the foregoing may appear in text,the embodiments may be practiced in many ways and the claims include anyequivalents thereof.

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to specific compositionsor process steps, as such can vary. As used in this specification andthe appended claims, the singular forms “a”, “an” and “the” includeplural referents unless the context clearly dictates otherwise. Theterms “a” (or “an”), as well as the terms “one or more,” and “at leastone” can be used interchangeably herein.

Furthermore, “and/or” where used herein is to be taken as specificdisclosure of each of the two specified features or components with orwithout the other. Thus, the term “and/or” as used in a phrase such as“A and/or B” herein is intended to include “A and B,” “A or B,” “A”(alone), and “B” (alone). Likewise, the term “and/or” as used in aphrase such as “A, B, and/or C” is intended to encompass each of thefollowing aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; Aand C; A and B; B and C; A (alone); B (alone); and C (alone).

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure is related. For example, the ConciseDictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed.,2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed.,1999, Academic Press; and the Oxford Dictionary Of Biochemistry AndMolecular Biology, Revised, 2000, Oxford University Press, provide oneof skill with a general dictionary of many of the terms used in thisdisclosure.

Units, prefixes, and symbols are denoted in their Système Internationalde Unites (SI) accepted form. Numeric ranges are inclusive of thenumbers defining the range.

It is understood that wherever aspects are described herein with thelanguage “comprising,” otherwise analogous aspects described in terms of“consisting of” and/or “consisting essentially of” are also provided.

The terms “inhibit,” “block,” and “suppress” are used interchangeablyherein and refer to any statistically significant decrease in biologicalactivity, including full blocking of the activity. For example,“inhibition” can refer to a decrease of about 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90% or 100% in biological activity.

Cellular proliferation can be assayed using art recognized techniqueswhich measure rate of cell division, and/or the fraction of cells withina cell population undergoing cell division, and/or rate of cell lossfrom a cell population due to terminal differentiation or cell death(e.g., thymidine incorporation).

The term “subject” refers to any animal (e.g., a mammal), including, butnot limited to humans, non-human primates, rodents, and the like, whichis to be the recipient of a particular treatment. Typically, the terms“subject” and “patient” are used interchangeably herein in reference toa human subject.

The term “pharmaceutical composition” refers to a preparation which isin such form as to permit the biological activity of the activeingredient, and which contains no additional components which areunacceptably toxic to a subject to which the composition would beadministered. Such composition can be sterile.

Terms such as “treating” or “treatment” or “to treat” or “alleviating”or “to alleviate” refer to both (1) therapeutic measures that cure, slowdown, lessen symptoms of, and/or halt progression of a diagnosedpathologic condition or disorder and (2) prophylactic or preventativemeasures that prevent and/or slow the development of a targetedpathologic condition or disorder. Thus, those in need of treatmentinclude those already with the disorder; those prone to have thedisorder; and those in whom the disorder is to be prevented. In certainaspects, a subject is successfully “treated” for cancer according to themethods of the present disclosure if the patient shows, e.g., total,partial, or transient remission of a certain type of cancer.

The terms “cancer”, “tumor”, “cancerous”, and “malignant” refer to ordescribe the physiological condition in mammals that is typicallycharacterized by unregulated cell growth. Examples of cancers includebut are not limited to, hematological malignancies such as acute myeloidleukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse largeB cell lymphoma, Burkitt's lymphoma, follicular lymphoma and solidtumors such as breast cancer, lung cancer, neuroblastoma and coloncancer.

The term “cytotoxic agent” as used herein is defined broadly and refersto a substance that inhibits or prevents the function of cells and/orcauses destruction of cells (cell death), and/or exertsanti-neoplastic/anti-proliferative effects. For example, cytotoxic agentprevents directly or indirectly the development, maturation, or spreadof neoplastic tumor cells. The term includes also such agents that causea cytostatic effect only and not a mere cytotoxic effect. The termincludes chemotherapeutic agents as specified below, as well as otherHER2 antagonists, anti-angiogenic agents, tyrosine kinase inhibitors,protein kinase A inhibitors, members of the cytokine family, radioactiveisotopes, and toxins such as enzymatically active toxins of bacterial,fungal, plant or animal origin.

The term “chemotherapeutic agent” is a subset of the term “cytotoxicagent” comprising natural or synthetic chemical compounds.

In accordance with the methods of the present disclosure, compounds ofthe present disclosure may be administered to a patient to promote apositive therapeutic response with respect to cancer. The term “positivetherapeutic response” with respect to cancer treatment refers to animprovement in the symptoms associated with the disease.

For example, an improvement in the disease can be characterized as acomplete response. The term “complete response” refers to an absence ofclinically detectable disease with normalization of any previously testresults. Alternatively, an improvement in the disease can be categorizedas being a partial response. A “positive therapeutic response”encompasses a reduction or inhibition of the progression and/or durationof cancer, the reduction or amelioration of the severity of cancer,and/or the amelioration of one or more symptoms thereof resulting fromthe administration of compounds of the present disclosure.

In specific aspects, such terms refer to one, two or three or moreresults following the administration of compounds of the instantdisclosure:

(1) a stabilization, reduction or elimination of the cancer cellpopulation;

(2) a stabilization or reduction in cancer growth;

(3) an impairment in the formation of cancer;

(4) eradication, removal, or control of primary, regional and/ormetastatic cancer;

(5) a reduction in mortality;

(6) an increase in disease-free, relapse-free, progression-free, and/oroverall survival, duration, or rate;

(7) an increase in the response rate, the durability of response, ornumber of patients who respond or are in remission;

(8) a decrease in hospitalization rate,

(9) a decrease in hospitalization lengths,

(10) the size of the cancer is maintained and does not increase orincreases by less than 10%, preferably less than 5%, preferably lessthan 4%, preferably less than 2%, and

(11) an increase in the number of patients in remission.

(12) a decrease in the number of adjuvant therapies (e.g., chemotherapyor hormonal therapy) that would otherwise be required to treat thecancer.

Clinical response can be assessed using screening techniques such asPET, magnetic resonance imaging (MRI) scan, x-radiographic imaging,computed tomographic (CT) scan, flow cytometry or fluorescence-activatedcell sorter (FACS) analysis, histology, gross pathology, and bloodchemistry, including but not limited to changes detectable by ELISA,RIA, chromatography, and the like. In addition to these positivetherapeutic responses, the subject undergoing therapy can experience thebeneficial effect of an improvement in the symptoms associated with thedisease.

In this specification the prefix C_(x-y) as used in terms such asC_(x-y)alkyl and the like (where x and y are integers) indicates thenumerical range of carbon atoms that are present in the group; forexample, C₁₋₄alkyl includes C₁alkyl (methyl), C₂alkyl (ethyl), C₃alkyl(propyl and isopropyl) and C₄alkyl (butyl, 1-methylpropyl,2-methylpropyl, and t-butyl).

Unless specifically stated, the bonding atom of a group may be anysuitable atom of that group; for example, propyl includes prop-1-yl andprop-2-yl.

As used herein, the phrase “optionally substituted,” indicates thatsubstitution is optional and therefore it is possible for the designatedgroup to be either substituted or unsubstituted. In the event asubstitution is desired, any number of hydrogens on the designated groupmay be replaced with a selection from the indicated substituents,provided that the normal valency of the atoms on a particularsubstituent is not exceeded, and that the substitution results in astable compound.

In one aspect, when a particular group is designated as being optionallysubstituted with “one or more” substituents, the particular group may beunsubstituted. In another aspect, the particular group may bear onesubstituent. In another aspect, the particular substituent may bear twosubstituents. In still another aspect, the particular group may bearthree substituents. In yet another aspect, the particular group may bearfour substituents. In a further aspect, the particular group may bearone or two substituents. In still a further aspect, the particular groupmay be unsubstituted, or may bear one or two substituents.

As used herein the term “alkyl” refers to both straight and branchedchain saturated hydrocarbon radicals having the specified number ofcarbon atoms. References to individual alkyl groups such as “propyl” arespecific for the straight chain version only and references toindividual branched chain alkyl groups such as “isopropyl” are specificfor the branched chain version only. In one aspect, “alkyl” may be“C₁₋₄alkyl.” In another aspect, “alkyl” and “C₁₋₄alkyl” may be“C₁₋₃alkyl.” In another aspect, “alkyl,” “C₁₋₄alkyl,” and “C₁₋₃alkyl,”may be methyl. An analogous convention applies to other generic terms,for example “alkenyl” and “alkynyl”.

“Cycloalkyl” is a monocyclic, saturated or partially unsaturated alkylring containing 3 to 7 carbon atoms. Illustrative examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

“Heterocycloalkyl” is a saturated or partially saturated monocyclic ringcontaining 3 to 7 ring atoms of which 1, 2, 3 or 4 ring atoms are chosenfrom nitrogen, sulphur or oxygen, which ring may be carbon or nitrogenlinked, wherein a —CH₂— group can optionally be replaced by a —C(O)—;wherein a ring nitrogen or sulphur atom is optionally oxidised to formthe N-oxide or S-oxide(s) (i.e. sulfoxide and sulfone); wherein a ring—NH is optionally substituted by acetyl, formyl, methyl or mesyl; andwherein a ring is optionally substituted by one or more halo.Illustrative examples of “5- or 6-membered heterocycloalkyl” include,imidazolinyl, pyrazolidinyl, piperazinyl, piperidinyl, pyrrolidinyl,oxazinyl, morpholinyl, hexahydropyrimidinyl, and thiomorpholinyl.

Suitable values for any R group (R¹ to R¹²) or any part or substituentfor such groups include:

for C₁₋₄alkyl: methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyland tert-butyl;

for C₁₋₆alkyl: C₁₋₄alkyl, pentyl, 2,2-dimethylpropyl, 3-methylbutyl andhexyl;

for C₃₋₇ cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and cycloheptyl;

for halo or halogen: fluoro, chloro, bromo and iodo;

for heterocycloalkyl: pyrrolidinyl, piperidinyl, N-acetylpiperidinyl,N-methylpiperidinyl, N-formylpiperazinyl, N-mesylpiperazinyl,homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl,pyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, 2,5-dioximidazolidinyl,and 2,2-dimethyl-1,3-dioxolanyl

It should be noted that examples given for terms used in the descriptionare not limiting.

As used herein, the phrase “effective amount” means an amount of acompound or composition which is sufficient enough to significantly andpositively modify the symptoms and/or conditions to be treated (e.g.,provide a positive clinical response). The effective amount of an activeingredient for use in a pharmaceutical composition will vary with theparticular condition being treated, the severity of the condition, theduration of the treatment, the nature of concurrent therapy, theparticular active ingredient(s) being employed, the particularpharmaceutically-acceptable excipient(s)/carrier(s) utilized, and likefactors within the knowledge and expertise of the attending physician.

In particular, an effective amount of a compound of Formula (I) for usein the treatment of cancer is an amount sufficient to symptomaticallyrelieve in a warm-blooded animal such as man, the symptoms of cancer andmyeloproliferative diseases, to slow the progression of cancer andmyeloproliferative diseases, or to reduce in patients with symptoms ofcancer and myeloproliferative diseases the risk of getting worse.

As used herein, the phrase “leaving group” is intended to refer togroups readily displaceable by a nucleophile such as an aminenucleophile, and alcohol nucleophile, or a thiol nucleophile. Examplesof suitable leaving groups include halo, such as chloro and bromo, andsulfonyloxy group, such as methanesulfonyloxy and toluene-4-sulfonyloxy.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, the term “protecting group” is intended to refer tothose groups used to prevent selected reactive groups (such as carboxy,amino, hydroxy, and mercapto groups) from undergoing undesiredreactions.

Illustrative examples of suitable protecting groups for a hydroxy groupinclude, but are not limited to acyl groups; alkanoyl groups such asacetyl; aroyl groups, such as benzoyl; silyl groups, such astrimethylsilyl; and arylmethyl groups, such as benzyl. The deprotectionconditions for the above hydroxy protecting groups will necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or an aroyl group may be removed, for example, byhydrolysis with a suitable base such as an alkali metal hydroxide, forexample lithium or sodium hydroxide. Alternatively a silyl group such astrimethylsilyl may be removed, for example, by fluoride or by aqueousacid; or an arylmethyl group such as a benzyl group may be removed, forexample, by hydrogenation in the presence of a catalyst such aspalladium-on-carbon.

Illustrative examples of suitable protecting groups for an amino groupinclude, but are not limited toacyl groups; alkanoyl groups such asacetyl; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl,and t-butoxycarbonyl; arylmethoxycarbonyl groups, such asbenzyloxycarbonyl; and aroyl groups, such benzoyl. The deprotectionconditions for the above amino protecting groups necessarily vary withthe choice of protecting group. Thus, for example, an acyl group such asan alkanoyl or alkoxycarbonyl group or an aroyl group may be removed forexample, by hydrolysis with a suitable base such as an alkali metalhydroxide, for example lithium or sodium hydroxide. Alternatively anacyl group such as a t-butoxycarbonyl group may be removed, for example,by treatment with a suitable acid as hydrochloric, sulfuric, phosphoricacid or trifluoroacetic acid and an arylmethoxycarbonyl group such as abenzyloxycarbonyl group may be removed, for example, by hydrogenationover a catalyst such as palladium-on-carbon, or by treatment with aLewis acid, for example boron trichloride. A suitable alternativeprotecting group for a primary amino group is, for example, a phthaloylgroup, which may be removed by treatment with an alkylamine, for exampledimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art,or they may be removed during a later reaction step or work-up.

With reference to substituent “R” for illustrative purposes, thefollowing substituent definitions refer to the indicated structure:

Within the present invention it is to be understood that a compound offormula (I) or a salt thereof may exhibit the phenomenon of tautomerismand that the formulae drawings within this specification can representonly one of the possible tautomeric forms. It is to be understood thatthe invention encompasses any tautomeric form which has CDK9 inhibitoryactivity and is not to be limited merely to any one tautomeric formutilised within the formulae drawings.

It is also to be understood that certain compounds of formula (I) andsalts thereof can exist in solvated as well as unsolvated forms such as,for example, hydrated forms. It is to be understood that the inventionencompasses all such solvated forms which have CDK9 inhibitory activity.

The compounds of formula (I) may also be provided as in vivohydrolysable esters. An in vivo hydrolysable ester of a compound offormula (I) containing carboxy or hydroxy group is, for example apharmaceutically acceptable ester which is cleaved in the human oranimal body to produce the parent acid or alcohol. Such esters can beidentified by administering, for example, intravenously to a testanimal, the compound under test and subsequently examining the testanimal's body fluid.

Suitable pharmaceutically acceptable esters for carboxy includeC₁₋₆alkoxymethyl esters for example methoxymethyl, C₁₋₆alkanoyloxymethylesters for example pivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkcarbonyloxy C₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl, (1,3-dioxolen-2-one)ylmethyl esters forexample (5-methyl-1,3-dioxolen-2-one)ylmethyl, andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl;and may be formed at any carboxy group in the compounds of thisinvention.

Suitable pharmaceutically acceptable esters for hydroxy includeinorganic esters such as phosphate esters (including phosphoramidiccyclic esters) and α-acyloxyalkyl ethers and related compounds which asa result of the in vivo hydrolysis of the ester breakdown to give theparent hydroxy groups. Examples of α-acyloxyalkyl ethers includeacetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of invivo hydrolysable ester forming groups for hydroxy includeC₁₋₁₀alkanoyl, for example acetyl, benzoyl, phenylacetyl, substitutedbenzoyl and phenylacetyl; C₁₋₁₀alkoxycarbonyl (to give alkyl carbonateesters), for example ethoxycarbonyl; di-C₁₋₄alkylcarbamoyl andN-(di-C₁₋₄alkylaminoethyl)-N—C₁₋₄alkylcarbamoyl (to give carbamates);di-C₁₋₄alkylaminoacetyl and carboxyacetyl. Examples of ring substituentson phenylacetyl and benzoyl include aminomethyl, C₁₋₄alkylaminomethyland di-(C₁₋₄alkyl)aminomethyl, and morpholino or piperazino linked froma ring nitrogen atom via a methylene linking group to the 3- or4-position of the benzoyl ring. Other interesting in vivo hydrolysableesters include, for example, R^(A)C(O)OC₁₋₆alkyl-CO—, wherein R^(A) isfor example, benzyloxy-C₁₋₄alkyl, or phenyl. Suitable substituents on aphenyl group in such esters include, for example,4-C₁₋₄alkylpiperazino-C₁₋₄alkyl, piperazino-C₁₋₄alkyl andmorpholino-C₁₋₄alkyl.

Compounds of Formula (I) may form stable pharmaceutically acceptableacid or base salts, and in such cases administration of a compound as asalt may be appropriate. Examples of acid addition salts includeacetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate,bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate,cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate,glutamate, glycolate, hemisulfate, 2-hydroxyethyl-sulfonate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate,lactate, malate, maleate, methanesulfonate, meglumine,2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate,phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate,quinate, salicylate, stearate, succinate, sulfamate, sulfanilate,sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate, andundecanoate. Examples of base salts include ammonium salts; alkali metalsalts such as sodium, lithium and potassium salts; alkaline earth metalsalts such as aluminum, calcium and magnesium salts; salts with organicbases such as dicyclohexylamine salts and N-methyl-D-glucamine; andsalts with amino acids such as arginine, lysine, ornithine, and soforth. Also, basic nitrogen-containing groups may be quaternized withsuch agents as: lower alkyl halides, such as methyl, ethyl, propyl, andbutyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl;diamyl sulfates; long chain halides such as decyl, lauryl, myristyl andstearyl halides; arylalkyl halides such as benzyl bromide and others.Non-toxic physiologically-acceptable salts are preferred, although othersalts may be useful, such as in isolating or purifying the product.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water, which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion-exchange resin.

Compounds of Formula (I) have chiral centers, and thus exist asstereoisomers. It is to be understood that the invention encompasses allsuch stereoisomers, including enantiomers and diastereoisomers. Insofaras compounds of Formula (I) may exist in optically active or racemicforms, the invention includes in its definition any such opticallyactive or racemic form which possesses the above-mentioned activity. Thepresent invention encompasses all such stereoisomers having activity asherein defined.

The synthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis from optically active starting materials or by resolution of aracemic form. Racemates may be separated into individual enantiomersusing known procedures (see, for example, Advanced Organic Chemistry:3rd Edition: author J March, p 104-107). A suitable procedure involvesformation of diastereomeric derivatives by reaction of the racemicmaterial with a chiral auxiliary, followed by separation, for example bychromatography, of the diastereomers and then cleavage of the auxiliaryspecies. Similarly, the above-mentioned activity may be evaluated usingthe standard laboratory techniques referred to hereinafter.

Thus, throughout the specification, where reference is made to thecompound of Formula (I), it is to be understood that the term compoundincludes stereoisomers, mixtures of stereoisomers, and polymorphs thatinhibit CDK9 activity in a human or animal.

Stereoisomers may be separated using conventional techniques, e.g.chromatography or fractional crystallisation. The enantiomers may beisolated by separation of a racemate for example by fractionalcrystallisation, resolution or HPLC. The diastereoisomers may beisolated by separation by virtue of the different physical properties ofthe diastereoisomers, for example, by fractional crystallisation, HPLCor flash chromatography. Alternatively particular stereoisomers may bemade by chiral synthesis from chiral starting materials under conditionswhich will not cause racemisation or epimerisation, or byderivatisation, with a chiral reagent.

When a specific stereoisomer is provided (whether provided byseparation, by chiral synthesis, or by other methods) it is favorablyprovided substantially isolated from other stereoisomers of the samecompound. In one aspect, a mixture containing a particular stereoisomerof a compound of Formula (I) may contain less than 30%, particularlyless than 20%, and more particularly less than 10% by weight of otherstereoisomer(s) of the same compound. In another aspect, a mixturecontaining a particular stereoisomer of a compound of Formula (I) maycontain less than 6%, particularly less than 3%, and more particularlyless than 2% by weight of other stereoisomer(s) of the compound. Inanother aspect, a mixture containing a particular stereoisomer of acompound of Formula (I) may contain less than 1%, particularly less than0.5%, and more particularly less than 0.3%, and still more particularlyless than 0.1% by weight of other stereoisomer(s) of the compound. Wherethe absolute configuration of isolated stereoisomers is not determined,stereoisomers may be differentiated by a method of preparation orseparation. For example, isolated stereoisomers may be differentiated bytheir elution time and denoted, for example, isomer 1, isomer 2, etc.

In accordance with the present invention compounds of the inventionoccur in a number of structurally different forms. It is an object ofthe present invention to provide a substantially pure crystal forms insome aspects of the invention.

Some structural forms of the invention may provide advantages. Forinstance, some forms of compound of the invention may be easier tohandle and store. Other forms of the compound of the invention may beeasier to characterize because it exists in a well defined state.Additionally, the compound of the invention may be easier to synthesizein a reproducible manner and thereby easier to handle in a full scaleproduction.

When a specific polymorphic form is provided, it is favorably providedsubstantially isolated from other polymorphic forms of the samecompound. In one aspect, a mixture containing a particular polymorphicform of a compound of Formula (I) may contain less than 30%,particularly less than 20%, and more particularly less than 10% byweight of other polymorphic forms of the same compound. In anotheraspect, a mixture containing a particular polymorphic form of a compoundof Formula (I) may contain less than 6%, particularly less than 3%, andmore particularly less than 2% by weight of other polymorphic forms ofthe compound. In another aspect, a mixture containing a particularpolymorphic form of a compound of Formula (I) may contain less than 1%,particularly less than 0.5%, and more particularly less than 0.3%, andstill more particularly less than 0.1% by weight of other polymorphicforms of the compound.

The compounds of the invention may be characterized by the positions andintensities of the major peaks in the X-ray powder diffractogram, butmay also be characterized by conventional FT-IR spectroscopy. These maybe used to distinguish one crystal form from other crystal forms of thecompound. The compounds of the invention are characterized by beinghighly crystalline, i.e. having a higher crystallinity than other forms.With the expression “any other form” is meant anhydrates, hydrates,solvates, and polymorphs or amorphous forms thereof disclosed in theprior art. Examples of any other forms of compounds include, but are notlimited to, anhydrates, monohydrates, dihydrates, sesquihydrates,trihydrates, alcoholates, such as methanolates and ethanolates, andpolymorphs or amorphous forms thereof.

The compound of the invention may also be characterized by its unitcell. The compound of the invention prepared according to the presentinvention may be analyzed by XRPD, a technique which is known per se.

The amount of water in the compound can be determined bythermogravimetric analysis, a technique which is known per se.

Additional embodiments of the invention are as follows. These additionalembodiments relate to compounds of Formula (I) and pharmaceuticallyacceptable salts thereof. Such specific substituents may be used, whereappropriate, with any of the definitions, claims or embodiments definedhereinbefore or hereinafter.

A

In one aspect, A is C(R⁵).

R⁵

In one aspect of the present invention R⁵ is halogen.

In one aspect of the present invention R⁵ is chloro.

In one aspect of the present invention R⁵ is fluoro.

In one aspect of the present invention R⁵ is cyano.

R²

In one aspect R² is 3-7 membered cycloalkyl.

In another aspect R² is 3-7 membered cycloalkyl substituted with NHCOR¹⁰or R¹⁰.

In another aspect R² is cyclohexyl substituted with NHCOR¹⁰.

In another aspect R² is cyclopropyl substituted with R¹⁰.

In another aspect R² is 3-7 membered heterocycloalkyl.

In another aspect R² is 3-7 membered heterocycloalkyl substituted withNHCOR¹⁰.

In another aspect R² is piperidinyl.

In another aspect R² is cyclobutyl.

In another aspect R² is cyclobutyl substituted with R¹⁰.

R⁴

In one aspect R⁴ is

In another aspect R⁴ is

In one aspect J is C(R¹¹) and R¹¹ is H.

X and Y

In one aspect X and Y together with the atoms to which they are attachedform a 6 membered heterocycloalkyl ring.

In one aspect X and Y together with the atoms to which they are attachedform a 6 membered heterocycloalkyl ring containing an additionalheteroatom which is oxygen.

In one aspect X and Y together with the atoms to which they are attachedform a 6 membered heterocycloalkyl ring containing an additionalheteroatom which is nitrogen.

In one aspect X and Y together with the atoms to which they are attachedform a 6 membered heterocycloalkyl ring in which one CH₂ is substitutedwith two methyl groups.

In one aspect X and Y together with the atoms to which they are attachedform a 5 membered heterocycloalkyl ring.

In one aspect X and Y together with the atoms to which they are attachedform a 5 membered heterocycloalkyl ring in which one CH₂ is substitutedwith two methyl groups.

In one aspect X and Y together with the atoms to which they are attachedform a 7 membered heterocycloalkyl ring.

In one aspect X and Y together with the atoms to which they are attachedform a 7 membered heterocycloalkyl ring in which one CH₂ is substitutedwith two methyl groups.

In one aspect

A is C(R⁵);

R² is 3-7 membered cycloalkyl;

R⁴ is

and

X and Y together with the atoms to which they are attached form a 6membered heterocycloalkyl ring.

In one aspect

A is C(R⁵);

R⁵ is halogen;

R² is 3-7 membered cycloalkyl;

R⁴ is

and

X and Y together with the atoms to which they are attached form a 6membered heterocycloalkyl ring.

In one aspect

A is C(R⁵);

R⁵ is chloro;

R² is 3-7 membered cycloalkyl;

R⁴ is

and

X and Y together with the atoms to which they are attached form a 6membered heterocycloalkyl ring.

In one aspect

A is C(R⁵);

R⁵ is chloro;

R² is cyclohexyl;

R⁴ is

and

X and Y together with the atoms to which they are attached form a 6membered heterocycloalkyl ring.

In one aspect

A is C(R⁵);

R⁵ is chloro;

R² is cyclohexyl substituted with NHC(O)R¹⁰;

R⁴ is

and

X and Y together with the atoms to which they are attached form a 6membered heterocycloalkyl ring.

In one aspect

A is C(R⁵);

R⁵ is chloro;

R² is cyclohexyl substituted with NHC(O)R¹⁰;

R¹⁰ is C₁₋₆ alkyl;

R⁴ is

J is C(R¹¹) and R¹¹ is H; and

X and Y together with the atoms to which they are attached form a 6membered heterocycloalkyl ring.

In one aspect

A is C(R⁵);

R² is 3-7 membered cycloalkyl;

R⁴ is

and

X and Y together with the atoms to which they are attached form a 5membered heterocycloalkyl ring.

In one aspect

A is C(R⁵);

R⁵ is halogen;

R² is cyclohexyl;

R⁴ is

and

X and Y together with the atoms to which they are attached form a 5membered heterocycloalkyl ring.

In one aspect

A is C(R⁵);

R⁵ is chloro;

R² is cyclohexyl;

R⁴ is

and

X and Y together with the atoms to which they are attached form a 5membered heterocycloalkyl ring.

In one aspect

A is C(R⁵);

R⁵ is chloro;

R² is cyclohexyl substituted with NHC(O)R¹⁰;

R⁴ is

and

X and Y together with the atoms to which they are attached form a 5membered heterocycloalkyl ring.

In one aspect

A is C(R⁵);

R⁵ is chloro;

R² is cyclohexyl substituted with NHC(O)R¹⁰;

R¹⁰ is C₁₋₆ alkyl;

R⁴ is

J is C(R¹¹) and R¹¹ is H; and

X and Y together with the atoms to which they are attached form a 5membered heterocycloalkyl ring.

In one aspect

A is C(R⁵);

R⁵ is chloro;

R² is cyclohexyl substituted with NHC(O)R¹⁰;

R¹⁰ is C₁₋₆ alkyl;

R⁴ is

J is C(R¹) and R¹¹ is H; and

X and Y together with the atoms to which they are attached form apiperidinyl ring.

In one aspect

A is C(R⁵);

R⁵ is chloro;

R² is cyclohexyl substituted with NHC(O)R¹⁰;

R¹⁰ is C₁₋₆ alkyl;

R⁴ is

J is C(R¹) and R¹¹ is H; and

X and Y together with the atoms to which they are attached form apiperidinyl ring wherein one ring carbon may be substituted by one ortwo R¹⁰ substituents.

In one aspect

A is C(R⁵);

R⁵ is chloro;

R² is cyclohexyl substituted with NHC(O)R¹⁰;

R¹⁰ is C₁₋₆ alkyl;

R⁴ is

J is C(R₅) and R₅ is H; and

X and Y together with the atoms to which they are attached form apiperazinyl ring.

In one aspect

A is C(R⁵);

R⁵ is chloro;

R² is cyclohexyl substituted with NHC(O)R¹⁰;

R¹⁰ is C₁₋₆ alkyl;

R⁴ is

J is C(R₅) and R₅ is H; and

X and Y together with the atoms to which they are attached form amorpholinyl ring.

In one aspect

A is C(R⁵);

R⁵ is chloro;

R² is cyclohexyl substituted with NHC(O)R¹⁰;

R¹⁰ is C₁₋₆ alkyl;

R⁴ is

J is C(R₅) and R₅ is H; and

X and Y together with the atoms to which they are attached form apyrrolidinyl wherein one CH₂ is substituted with two methyl groups.

In one aspect

A is C(R⁵);

R² is 3-membered cycloalkyl;

R⁴ is

and

X and Y together with the atoms to which they are attached form a 7membered heterocycloalkyl ring.

In one aspect

A is C(R⁵);

R⁵ is halogen;

R² is 3-7 membered cycloalkyl;

R⁴ is

and

X and Y together with the atoms to which they are attached form a 7membered heterocycloalkyl ring.

In one aspect

A is C(R⁵);

R⁵ is chloro;

R² is 3-7 membered cycloalkyl;

R⁴ is

and

X and Y together with the atoms to which they are attached form a 7membered heterocycloalkyl ring.

In one aspect

A is C(R⁵);

R⁵ is chloro;

R² is cyclohexyl;

R⁴ is

and

X and Y together with the atoms to which they are attached form a 7membered heterocycloalkyl ring.

In one aspect

A is C(R⁵);

R⁵ is chloro;

R² is cyclohexyl substituted with NHC(O)R¹⁰;

R⁴ is

and

X and Y together with the atoms to which they are attached form a 7membered heterocycloalkyl ring.

In one aspect

A is C(R⁵);

R⁵ is chloro;

R² is cyclohexyl substituted with NHC(O)R¹⁰;

R¹⁰ is C₁₋₆ alkyl;

R⁴ is

J is C(R¹¹) and R¹¹ is H; and

X and Y together with the atoms to which they are attached form a 7membered heterocycloalkyl ring.

In another aspect of the invention there is provided a compound selectedfrom:

-   (R)—N-(5-chloro-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)piperidine-3-carboxamide;-   (1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   Cis-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide;-   (R)—N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)piperidine-3-carboxamide;-   cis-3-hydroxy-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclobutanecarboxamide;-   (1S,3R)-3-acetamido-N-(5-chloro-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;    (1R,3S)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(5-chloro-4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)—N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide;-   N-((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide;-   N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide;-   (1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-((S)-2-hydroxypropanamido)cyclohexanecarboxamide;-   (1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (R)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide;-   (S)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide;-   (1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide;-   cis-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide;-   cis-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide;-   (1S,3R)-3-acetamido-N-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)cyclohexanecarboxamide;-   trans-3-hydroxy-N-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)cyclobutanecarboxamide;-   (1S,3R)-3-acetamido-N-(6-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)cyclohexanecarboxamide;-   (1S,3R)—N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(2-cyanoacetamido)cyclohexanecarboxamide;-   tert-butyl    ((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate;-   (1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)—N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide;-   (R)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide;-   N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)-3-methyloxetane-3-carboxamide;-   (S)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide;-   (R)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide;-   (1S,3R)—N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-((S)-2-hydroxypropanamido)cyclohexanecarboxamide;-   (S)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide;-   (1S,3R)-3-acetamido-N-(5-cyano-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   Isomer 1 of    (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   Isomer 2 of    (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1R,3S)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (S)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide;-   (R)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide;-   (1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-methylpyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclopentanecarboxamide;-   (1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydro-[1,2,3]    triazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-amino-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(3-hydroxypropanamido)cyclohexanecarboxamide;-   (1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(cis-3-hydroxycyclobutanecarboxamido)cyclohexanecarboxamide-   (1S,3R)-3-amino-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide;-   (1S,3R)—N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide;-   (1S,3R)—N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide;-   N-((1R,3S)-3-((5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide;-   cis-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide;-   Isomer 1 of    trans-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   Isomer 2 of    trans-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   Isomer 1 of    trans-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   Isomer 2 of    trans-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(5-fluoro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   Isomer 1 of    (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   Isomer 2 of    (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(5-chloro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide;-   Isomer 1 of    (1S,3R)-3-acetamido-N-(5-chloro-4-(6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   Isomer 2 of    (1S,3R)-3-acetamido-N-(5-chloro-4-(6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   Isomer 1 of    (1S,3R)-3-acetamido-N-(5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   Isomer 2 of    (1S,3R)-3-acetamido-N-(5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   Isomer 1 of    (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   Isomer 2 of    (1S,3R)-3-acetamido-N-(5-chloro-4-(5-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(5-fluoro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)—N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-methylpyridin-2-yl)-3-(2-hydroxyacetamido)cyclohexanecarboxamide;-   N-((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide;-   (1S,3R)-3-acetamido-N-(5-methyl-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(5-chloro-4-(7-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(5-chloro-4-(5-(4-hydroxybutyl)-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexanecarboxamide;-   Isomer 1 of    (1S,3R)-3-acetamido-N-(5-chloro-4-(4-hydroxy-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   Isomer 2 of    (1S,3R)-3-acetamido-N-(5-chloro-4-(4-hydroxy-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;-   (1R,3S)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide;-   (1S,3R)-3-acetamido-N-(5-chloro-4-(5-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1-carboxamide;-   (1S,3R)-3-acetamido-N-(5-chloro-4-(6-hydroxy-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexane-1-carboxamide;-   (1R,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide;    and-   (1S,3S)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide.

The compounds of Formula (I) are useful for their ability to inhibitCDK9 activity. The compounds are also useful for the treatment of cancerin a patient. In accordance with those aspects of the inventioncompounds of Formula I, or a pharmaceutically acceptable salt thereof,may be administered to a patient suffering from a cancer such ashematological malignancies including acute myeloid leukemia, multiplemyeloma, chronic lymphocytic leukemia, diffuse large B cell lymphoma,Burkitt's lymphoma, follicular lymphoma and solid tumors such as breastcancer, lung cancer, neuroblastoma and colon cancer.

The compounds of Formula (I) have been shown to inhibit CDK9 activity asdemonstrated by an assay based on the assay description below. Althoughthe pharmacological properties of the compounds of the Formula (I) mayvary with structural change, typical compounds of the Formula (I)possess CDK9 inhibitory activity at IC₅₀ concentrations (concentrationsto achieve 50% inhibition) or doses at a level below 10 μM.

CDK9 Kinase Assay

ATP Concentration at Km

Activity of CDK9 was determined in-vitro using a mobility shift assay ona Caliper LC3000 reader (Caliper/PerkinElmer), which measuresfluorescence of a phosphorylated and unphosphorylated fluorescentpeptide substrate and calculates a ratiometric value to determinepercent turnover. Phosphorylation of the peptide in the presence andabsence of the compound of interest was determined.Enzyme/substrate/adenosine triphosphate (ATP) mix (3 nM CDK9/CycT1, 6 μMATP, 1.5 μM CDK9 peptide substrate (FITC-X-GSRTPMY-NH₂ (X: epsilonaminocaproic acid)), 50 mM HEPES (pH7.2), 1 mM dithiothreitol, 0.01%tween 20, 50 μg/mL bovine serum albumin, (final assay concentration)) (5μl) was preincubated with 2 μl of compound for 15 minutes at 25° C.Reactions were initiated with 5 μl of 24 mM MgCl₂ (10 mM final assayconcentration) in buffer (50 mM HEPES (pH7.2), 1 mM dithiothreitol,0.01% tween 20, 50 μg/mL bovine serum albumin, (final assayconcentration) and incubated at 25° C. for 90 minutes and reactions werestopped by addition of 5 μl of Stop mix consisting of 65 mM HEPES(pH7.2), 35.5 mM EDTA, 0.227% Coatin Reagent 3 (Caliper/PerkinElmer),and 0.003% Tween. Phosphorylated and unphosphorylated substrate wasdetected by a Caliper LC3000 reader (Caliper/PerkinElmer) in thepresence of separation buffer consisting of 100 mM HEPES (pH7.2), 15.8mM EDTA, 0.1% Coatin Reagent 3 (Caliper/PerkinElmer), 0.015% Brij-35, 5%DMSO, and 5.6 mM MgCl₂. CDK9 enzyme was acquired from Carna Biosciences(Catalogue number 04-110), the CDK9 peptide substrate was acquired fromIntonation (Boston, Mass.; Custom-made).

IC₅₀ values were calculated using standard curve fitting methods, withthe maximum signal being defined as the turnover from the inhibitedreaction at 83.3 mM EDTA and the minimum signal being defined as theturnover from the reaction at 0.83% DMSO.

High ATP Concentration

High ATP assays were run the same way with the following modifications:the final assay concentration of CDK9 was 1.5 nM and the final assayconcentration of ATP was 5 mM.

MCF7 pSer2 RNAPII MOA Assay

This is an immunofluorescence assay to determine the effect of CDK9inhibitors on phosphorylation of RNA Polymerase II (RNAPII) at the Ser2site in the breast cancer cell line, MCF7. On day one, 2500 MCF7cells/well were seeded in 30 μl of growth media (RPMI+10% FBS+1%L-Glu+P/S) in 384-well black-wall clear-bottom plates, incubate platesovernight at 37° C. incubator. On the second day, the cells were treatedwith CDK9 inhibitors (7 point dose response ranging from 3 μM to 0.004μM) using an ECHO liquid handler (Labcyte). After 6-hr treatment at 37°C. incubator, the cells were fixed with 30 l/well 7.4% paraformaldehydefor 15 min at room temperature; the cells were washed twice with PBS,then permeabilized with 0.3% Triton X/PBS for 5 min at room temperature.After washing cells with PBS, the cells were incubated with 1:2000diluted Anti-Ser2 Phospho-RNA pol II antibody (Covance MMS-129R) in 3%FBS/0.1% PBST overnight at 4° C. On the next day, the cells were washedtwice with 0.1% PBST, then incubated with 1:1000 diluted Alexa Fluor 488Goat-anti-mouse antibody (Life Technologies A-11001) and 1:4000 dilutedDAPI at room temperature in dark. After one hour incubation, the cellswere washed twice with 0.1% PBST, and once with PBS. The plates wheresealed and read on an Acumen eX3 microplate cytometer (TTP Labtech) toassess phosphorylation level in each well. The IC₅₀ values werecalculated using GeneData analysis software (DMSO control as maximum and11 μM Dinaciclib control as minimum).

MV411 Caspase Activity Assay

This is a cell assay to measure the induction of caspase activity in theacute myeloid leukemia cell line, MV411 after 6-hr treatment with CDK9inhibitors. On the first day, 3000 MV411 cells/well were seeded in 50 μlof growth media (IMDM+10% FBS+2% L-Glu+P/S) in 384-well white plates,incubate plates in 37° C. incubator overnight. On the second day, thecells were treated with CDK9 inhibitors by ECHO (10 point dose responseranging from 31.5 μM down to 0.001 μM). After 6 hour incubation in 37°C. incubator, 25 μl of Caspase-Glo 3/7 reagent (Promega) per well wasadded into each well, and plates were incubated at room temperature for30 min in dark. The plates were read on an Infinite M200 microplatereader (Tecan) with a 100 ms integration time. EC₅₀ values werecalculated using GeneData analysis software (DMSO control as Min and 11μM Dinaciclib control as Max).

Table I provides data for the assays.

TABLE I CDK9 CDK9 MV4-11 ATP conc. at High p-Ser 2 Caspase Km ATP conc.RNAPII Activity Example (IC₅₀, μM) (IC₅₀, μM) (IC₅₀, μM) (IC₅₀, μM) 10.0491 4.5 1.539 1.777 2 <0.003 0.040 0.13 0.12 3 <0.003 0.21 0.52 0.444 0.003 0.17 0.22 0.28 5 <0.004 0.27 0.26 0.16 6 0.008 0.75 0.46 0.63 70.008 0.69 1.45 1.181 8 <0.003 0.12 0.69 0.256 9 0.039 2.5 >3 4.089 100.005 0.217 0.55 0.333 11 0.011 1.20 2.7 1.934 12 0.005 0.35 0.83 0.70113 0.006 0.24 0.82 0.914 14 <0.003 <0.004 0.023 0.014 15 0.005 0.35 1.30.669 16 <0.003 0.028 0.15 0.10 17 0.004 0.036 0.207 0.14 18 <0.0030.014 0.122 0.071 19 <0.003 <0.003 0.013 0.011 20 <0.003 <0.003 0.010.014 21 <0.003 <0.003 <0.007 0.013 22 <0.003 0.011 0.036 0.054 23<0.003 <0.003 0.006 0.012 24 <0.003 0.004 0.011 0.015 25 <0.003 0.0040.025 0.029 26 <0.003 0.093 0.122 0.152 27 <0.003 0.025 0.044 0.038 280.036 4.714 >3.000 6.599 29 0.063 7.543 >2.631 7.22 30 0.007 0.606 1.2451.054 31 <0.003 0.012 0.036 0.09 31a <0.003 0.016 0.17 0.177 31b 0.0362.645 1.8 32 <0.003 0.017 0.055 0.136 33 <0.003 0.019 0.057 0.171 34<0.003 0.029 0.107 0.188 35 <0.003 0.023 0.04 0.125 36 <0.003 0.0390.038 0.104 37 <0.003 0.038 0.149 0.177 38 <0.003 0.028 0.123 0.139 39<0.003 0.062 0.147 0.145 40 <0.003 0.028 0.057 0.067 41 <0.003 0.0270.076 0.077 42 <0.003 0.026 0.036 0.092 43 0.007 0.287 0.307 0.416 44<0.003 0.008 0.048 0.039 45 <0.003 <0.004 0.012 0.008 46 <0.003 <0.0040.009 0.012 47 <0.003 0.022 0.04 0.074 48 <0.003 0.003 0.04 0.015 490.039 4.396 >2.867 7.977 50 <0.003 0.005 0.019 0.026 51 <0.003 <0.0030.01 0.015 51a <0.003 0.148 0.292 0.228 52 <0.003 0.004 53 <0.003 <0.0030.012 0.013 54 0.01 0.777 0.455 0.431 55 <0.003 <0.003 0.007 0.01 56<0.003 0.004 0.029 0.022 57 <0.003 0.004 0.028 0.053 58 <0.003 0.0410.017 0.076 59 0.051 6.819 >2.435 4.839 60 <0.003 0.017 0.049 0.068 610.215 21.208 >3.000 >31.500 62 0.004 0.169 0.333 0.615 63 <0.003 0.0510.104 0.159 64 <0.003 0.007 0.045 0.043 65 <0.003 <0.004 0.037 0.048 66<0.003 0.023 0.092 0.183 67 <0.003 0.019 0.062 0.099 68 <0.003 0.0530.131 0.166 69 0.005 0.246 0.193 0.792 70 <0.003 0.02 0.073 0.107 710.016 1.722 >2.348 4.828 72 0.003 0.111 0.36 0.4 73 <0.003 0.039 0.2180.447 74 <0.003 0.039 0.192 0.281 75 <0.003 0.029 0.067 0.111 76 <0.0030.009 0.038 0.036 77 0.004 0.213 0.338 0.543 78 <0.003 0.06 0.72 1.22778a <0.003 0.085 >2.628 7.13 79 <0.003 <0.003 0.01 0.015 80 0.004 0.1350.247 0.318 81 0.008 0.554 0.665 0.896 82 <0.004 0.022 0.174 0.124 82a0.004 0.139 >2.337 2.256 83 <0.003 0.025 0.061 0.073 84 0.0282.134 >1.947 2.518

In one aspect, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use as a medicament.

In another aspect, there is provided the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for the treatment or prophylaxis of at least one of:hematological malignancies such as acute myeloid leukemia, multiplemyeloma, chronic lymphocytic leukemia, diffuse large B cell lymphoma,Burkitt's lymphoma, follicular lymphoma and solid tumors such as breastcancer, lung cancer, neuroblastoma and colon cancer.

In another aspect, there is provided the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for the treatment of cancer.

In another aspect, there is provided the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for the production of an anti-proliferative and/orpro-apoptotic effect in a warm-blooded animal such as man.

In another aspect, there is provided the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for the production of a CDK9 inhibitory effect in a warmblooded animal such as man.

In another aspect, there is provided a method for the treatment orprophylaxis of at least one of hematological malignancies such as acutemyeloid leukemia, multiple myeloma, chronic lymphocytic leukemia,diffuse large B cell lymphoma, Burkitt's lymphoma, follicular lymphomaand solid tumors such as breast cancer, lung cancer, neuroblastoma andcolon cancer.

In another aspect, there is provided a method for producing ananti-proliferative and/or pro-apoptotic effect in a warm-blooded animalsuch as man, said method comprising administering to said animal aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof.

In another aspect, there is provided a method for producing a CDK9inhibitory effect in a warm-blooded animal such as man, said methodcomprising administering to said animal an effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another aspect, there is provided a method for treating cancer in awarm-blooded animal such as man, said method comprising administering tosaid animal an effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof.

In another aspect, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment of atleast one of: hematological malignancies such as acute myeloid leukemia,multiple myeloma, chronic lymphocytic leukemia, diffuse large B celllymphoma, Burkitt's lymphoma, follicular lymphoma and solid tumors suchas breast cancer, lung cancer, neuroblastoma and colon cancer.

In another aspect, there is provided a pharmaceutical compositioncomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and at least one pharmaceutically acceptable carrier,diluent, or excipient.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more coloring, sweetening, flavoring and/or preservativeagents.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate; granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate; andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form or in the form of nano or micronized particles togetherwith one or more suspending agents, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents such as lecithin or condensation productsof an alkylene oxide with fatty acids (for example polyoxethylenestearate), or condensation products of ethylene oxide with long chainaliphatic alcohols, for example heptadecaethyleneoxycetanol, orcondensation products of ethylene oxide with partial esters derived fromfatty acids and a hexitol such as polyoxyethylene sorbitol monooleate,or condensation products of ethylene oxide with long chain aliphaticalcohols, for example heptadecaethyleneoxycetanol, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand a hexitol such as polyoxyethylene sorbitol monooleate, orcondensation products of ethylene oxide with partial esters derived fromfatty acids and hexitol anhydrides, for example polyethylene sorbitanmonooleate. The aqueous suspensions may also contain one or morepreservatives such as ethyl or propyl p-hydroxybenzoate; anti-oxidantssuch as ascorbic acid; coloring agents; flavoring agents; and/orsweetening agents such as sucrose, saccharine or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as arachis oil, olive oil, sesame oil or coconutoil or in a mineral oil such as liquid paraffin. The oily suspensionsmay also contain a thickening agent such as beeswax, hard paraffin orcetyl alcohol. Sweetening agents such as those set out above, andflavoring agents may be added to provide a palatable oral preparation.These compositions may be preserved by the addition of an anti-oxidantsuch as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavoring and coloring agents,may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavoring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavoring and/or coloring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of aconventional pressurized aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 4 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

As stated above the size of the dose required for the therapeutic orprophylactic treatment of a particular disease state will necessarily bevaried depending on the host treated, the route of administration andthe severity of the illness being treated. A daily dose in the range of0.1-50 mg/kg may be employed. Accordingly, the optimum dosage may bedetermined by the practitioner who is treating any particular patient.

The compounds of the invention can be further administered incombination with a therapeutically effective amount of one or moreagents to treat a cancer, where examples of the agents include, such asradiation, alkylating agents, angiogenesis inhibitors, antibodies,antimetabolites, antimitotics, antiproliferatives, antivirals, aurorakinase inhibitors, cell death activators (for example, inhibitors ofBcl-2, Bcl-xL, Bcl-w, Bfl-1, or Mcl-1), activators of death receptorpathway, Bcr-Abl kinase inhibitors, BET (bromodomain) inhibitors, BiTE(Bi-Specific T cell Engager) antibodies, antibody drug conjugates,biologic response modifiers, cyclin-dependent kinase inhibitors, cellcycle inhibitors, cyclooxygenase-2 inhibitors, DVDs (dual variabledomain antibodies), leukemia viral oncogene homolog (ErbB2) receptorinhibitors, growth factor inhibitors, heat shock protein (HSP)-90inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies,immunologicals, inhibitors of inhibitors of apoptosis proteins (IAPs),intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2inhibitors, mammalian target of rapamycin inhibitors, microRNA's,mitogen-activated extracellular signal-regulated kinase inhibitors,multivalent binding proteins, non-steroidal anti-inflammatory drugs(NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase (PARP)inhibitors, platinum chemotherapeutics, polo-like kinase (Plk)inhibitors, phosphoinositide-3 kinase inhibitors, proteosome inhibitors,purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors,etinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids(siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, and thelike, and in combination with one or more of these agents.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,bendamustine, brostallicin, busulfan, cisplatin, carboplatin,carboquone, carmustine (BCNU), chlorambucil, CLORETAZINE® (laromustine,VNP 40101M), cyclophosphamide, decarbazine, estramustine, fotemustine,glufosfamide, ifosfamide, KW-2170, lomrustine (CCNU), mafosfanmide,melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustardN-oxide, nitrosoureas, oxaliplatin, ranimustine, temozolomide, thiotepa,TREANDA® (bendamustine), treosulfan, rofosfamide and the like.

Angiogenesis inhibitors include endothelial-specific receptor, (Tie-2)inhibitors, epidermal growth factor receptor (EGFR) inhibitors, insulingrowth factor-2 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2(MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors,platelet-derived growth factor receptor (PDGFR) inhibitors,thrombospondin analogs, vascular endothelial growth factor receptortyrosine kinase (VEGFR) inhibitors, ALK inhibitors and the like.

Antimetabolites include ALIMTA® (pemetrexed disodium, LY231514, MTA),5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine),clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside,decitabine, deferoxamine, doxifluridine, eflornithine, EICAR(5-ethynyl-1-β-D-ribofuranosylimidazole-4-arboxamide), enocitabine,ethnyicytidine, fludarabine, 5-fluorouracil alone or in combination withleucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan),mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolicacid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,pernextred, raltitrexed, Ribavirin, triapine, trimetrexate, S-1,tiazofurin, tegafur, TS-1, vidarabine, UFT and the like.

Bcl-2 protein inhibitors include ABT-199, AT-101 ((−)gossypol),GENASENSE® (G3139 or oblimersen (Bcl-2-targeting antisenseoligonucleotide)), IPI-194, IPI-565,N-(4-(4-((4′-chloro(1,1-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)(ABT-737),N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide(ABT-263), GX-070 (obatoclax) and the like.

Bromodomain inhibitors include I-BET 762, OTX-015, CPI-203, LY294002 andthe like.

CDK inhibitors include BMI-1040, BMS-032, BMS-387, CVT-2584,flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib(CYC-202, R-roscovitine), ZK-304709 and the like.

EGFR inhibitors include EGFR antibodies, ABX-EGF, anti-EGFRimmunoliposomes, EGF-vaccine, EM D-7200, ERBITUX® (cetuximab), HR3, IgAantibodies, IRESSA® (gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38,EGFR fusion protein, TYKERB® (lapatinib), AZD9291, and the like.

ALK inhibitors include crizotinib, ceritinib, and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4,petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166,dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HEIR/2neubispecific antibody, B7.her2IgG3, as HER2 bifunctional bispecificantibodies, mAB AR-209, mAB 2B-1 and the like.

Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-M MAE,anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35,SGN-75 and the like.

Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520;CENPE inhibitors such as GSK923295A and the like.

MEK inhibitors include ARRY-142886, ARRY-438162, PD-325901, PD-98059,selumitinib, and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin)eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin),satraplatin, picoplatin and the like.

VEGFR inhibitors include AVASTIN (bevacizumab), ABT-869, AEE-788,ANGIOZYME™ (a ribozyme that inhibits angiogenesis (RibozymePharmaceuticals (Boulder, Colo.) and Chiron, (Emeryville, Calif.)),axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib),NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib(PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap, ZACTIMA™(vandetanib, ZD-6474), GA101, ofatumumab, ABT-806 (mAb-806), ErbB3specific antibodies, BSG2 specific antibodies, DLL4 specific antibodiesand C-met specific antibodies, and the like.

Antitumor antibiotics include intercalating antibiotics aclarubicin,actinomycin D, armubicin, annamycin, adriamycin, BLENOXANE® (bleomycin),daunorubicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitrucin,epirbucin, glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin,neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer,streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Inhibitors of DNA repair mechanisms such as CHK kinase; DNA-dependentprotein kinase inhibitors; inhibitors of poly (ADP-ribose) polymerase(PARP inhibitors) including ABT-888 (veliparib), olaparib, KU-59436,AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like;and Hsp90 inhibitors such as tanespimycin and retaspimycin.

Proteasome inhibitors include VELCADE® (bortezornib), carfilzomib,MG132, NPI-0052, PR-171 and the like.

Examples of immunologicals include interferons and otherimmune-enhancing agents. Interferons include interferon alpha,interferon alpha-2a, interferon alpha-2b, interferon beta, interferongamma-1a, ACTIMMUNE® (interferon gamma-1b) or interferon gamma-n1,combinations thereof and the like. Other agents include ALFAFERONE®,(IFN-α), BAM-002 (oxidized glutathione), BEROMUN® (tasonermin), BEXXAR®(tositumomab), CAMPATH® (alemntuzumab), CTLA4 (cytotoxic lymphocyteantigen 4), decarbazine, denileukin, epratuzumab, GRANOCYTE®(lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010(anti-CTLA-4), melanoma vaccine, mitumomnab, molgramostim, MYLOTARG™(gemtuzumab ozogamicin), NEUPOGEN® (filgrastim), OncoVAC-CL, OVAREX®(oregovomab), pemtumomab (Y-muHMFG1), PROVENGE® (sipuleucel-T),sargaramostim, sizofilan, teceleukin, THERACYS® (BacillusCalmette-Guerin), ubeninex, VIRULIZIN® (immunotherapeutic, LorusPharmaceuticals), Z-100 (Specific Substance of Maruyama (SSM)), WF-10(Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZADAXIN®(thymalfasin), ZENAPAX® (daclizumrab), ZEVALIN® (90Y-Ibritumomabtiuxetan) and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosinearabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU(5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX®(ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.

Antimitotic agents include batabulin, epothilone D (KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU 100940(109881), patupilone, XRP-9881 (Iarotaxel), vinflunine, ZK-EPO(synthetic epothilone) and the like.

Additionally, compounds having Formula (I) may be combined with otherchemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (farnesyltransferase inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® orMEVACOR® (lovastatin), AMPLIGEN® (poly I:poly C12U, a synthetic RNA),APTOSYN® (exisulind), AREDIA® (pamidronic acid), arglabin.L-asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene),AVAGE® (Lazarotene), AVE-8062 (combreastatin derivative) BEC2(mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin(vaccine), CEAVAC® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE®(histamine dihydrochloride), CERVARIX® (human papillomavirus vaccine),CHOP® (C: CYTOXAN® (cyciophosphamide); H: ADRIAMYCIN®(hydroxydoxorubicin); O: Vincristine (ONCOVIN®); P: prednisone), CYPAT™(cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic andtranslocation domains of diphtheria toxin fused via a His-Ala linker tohuman epidermal growth factor) or TransMID-107R™ (diphtheria toxins),dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA),eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposomelotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin,EPO906 (epithilone B), GARDASIL® (quadrivalent human papillomavirus(Types 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®,GMK (ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine),halofugi none, histerelin, hydroxycarbamide, ibandronic acid, IGN-101,IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonasexotoxin, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide),lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine(hexadecylphosphocholine), NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexateglucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme),ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine),ORATHECIN™ (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb(murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponinsfrom ginseng comprising 20(S)protopanaxadiol (aPPD) and20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigationalcancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol,procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID®(lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide),SORIATANE® (acitretin), staurosporine (Streptomyces staurospores),talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN®(DHA-paclitaxel), TELCYTA® (canfosfamride, TLK286), temilifene. TEMODAR®(temozolomide), tesmilifene, thalidomide. THERATOPE® (STn-KLH), thymitaq(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthlio)quinazolinedihydrochloride), TNFERADE™ (adenovector: DNA carrier containing thegene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan),tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandineplant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® (motexafingadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex),YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA®(zolendronic acid), zorubicin and the like.

Herein, where the term “combination” is used it is to be understood thatthis refers to simultaneous, separate or sequential administration. Inone embodiment of the invention “combination” refers to simultaneousadministration. In another embodiment of the invention “combination”refers to separate administration. In a further embodiment of theinvention “combination” refers to sequential administration. Where theadministration is sequential or separate, the delay in administering thesecond component should not be such as to lose the beneficial effect ofthe combination. Such combination products employ the compounds of thisinvention, or pharmaceutically acceptable salts thereof, within thedosage range described hereinbefore and the otherpharmaceutically-active agent within its approved dosage range. Thecombination therapy can provide “synergy” and prove “synergistic”, i.e.,the effect achieved when the active ingredients used together is greaterthan the sum of the effects that results from using the compoundsseparately. A synergistic effect can be attained when the activeingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined, unit dosage formulation; (2) delivered byalternation or in parallel as separate formulations; or (3) by someother regimen. When delivered in alternation therapy, a synergisticeffect can be attained when the compounds are administered or deliveredsequentially, e.g., by different injections in separate syringes. Ingeneral, during alternation therapy, an effective dosage of each activeingredient is administered sequentially, i.e., serially, whereas incombination therapy, effective dosages of two or more active ingredientsare administered together.

In any of the above-mentioned pharmaceutical composition, process,method, use, medicament, and manufacturing features of the instantinvention, any of the alternate embodiments of the compounds of theinvention described herein also apply.

In another aspect of the invention compounds of Formula (I) are preparedin accordance with the following general routes.

Route A

Some compounds of Formula (I) may be obtained from another compound ofFormula (I); for example, if containing an amino group, by acylation(conditions well known in the art), where A, R², and R⁴ are as definedfor formula (I).

Note that suitable protecting groups may be used in any routes such asthose well known in the art: for instance, for amino: t-butoxycarbonylor (trimetylsilyl)ethoxymethyl (SEM); for hydroxyl:tert-butyldimethylsilyl or tetrahydropyran-2-yl. Deprotection conditionsare well known in the art.

Route B

Other compounds of Formula (I) may be prepared by the reaction of acompound of Formula (II):

where L is a halogen atom (for example chloro) or a triflate group witha compound of formula (III):

The reaction may be performed under standard conditions well known tothose skilled in the art, for example in the presence of a palladiumsource (for example tetrakis(triphenylphosphine)palladium(0) orpalladium(II) acetate), optionally a phosphine ligand (for exampleXantphos), and a suitable base (for example cesium carbonate).

Compound of Formula (II) may be prepared by the reaction of a compoundof Formula (IV)

and a compound of Formula (V)R⁴-L

Y is a boronic acid, boronic ester or potassium trifluoroborate group(for example boronic acid, boronic acid pinacol ester, or potassiumtrifluoroborate) and L is a halogen atom (for example chloro or bromo)or a triflate group. The reaction may be performed under standardconditions well known to those skilled in the art, for example in thepresence of a palladium source and a phosphine ligand (for exampletetrakis(triphenylphosphine)palladium(0),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), also knownas Pd(dppf)Cl₂, and a suitable base (for example cesium carbonate orpotassium phosphate)).

Alternatively, Compound of Formula (II) may be prepared by the reactionof a compound of Formula (XIV)

and a compound of Formula (IX):R⁴—Y

Y is a boronic acid, boronic ester or potassium trifluoroborate group(for example boronic acid, boronic acid pinacol ester, or potassiumtrifluoroborate), L¹ and L² are a halogen atom or a triflate group,where L¹ is less reactive than L² during the coupling reaction, forexample where L¹ is chloro and L² is iodo. The reaction may be performedunder standard conditions well known to those skilled in the art, forexample in the presence of a palladium source and a phosphine ligand(for example 2^(nd) Generation XPhos Precatalyst, and a suitable base,for example potassium phosphate).

Alternatively, Compound of Formula (II) may be prepared by the reactionof a compound of Formula (XIV) and a compound of Formula (XII): R⁴—H,where L¹ and L² are a halogen atom or a triflate group, where L¹ is lessreactive than L² during the coupling reaction, for example where L¹ ischloro and L² is iodo, by a “C—H activation” reaction, for example asdescribed in Example Intermediate 50.

Route C

Some compounds of Formula (I) may for example be prepared by thereaction of a compound of Formula (VI)

with a compound of Formula (VII):

Suitable coupling agents for this reaction include for example,1-chloro-N,N,2-trimethylprop-1-en-1-amine,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate also known as HATU, TBTU(2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouroniumtetrafluoroborate), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride ion or 1-propanephosphonic anhydride (T₃P), preferably1-chloro-N,N,2-trimethylprop-1-en-1-amine or 1-propanephosphonicanhydride (T₃P).

The reaction is conveniently carried out in the presence of a suitablebase. A suitable base is, for example, an organic amine base such as,for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, N-methylmorpholine, diazabicyclo[5.4.0]undec-7-ene,diisopropylethyl amine, or, for example, an alkali or alkaline earthmetal carbonate or hydroxide, for example sodium carbonate, potassiumcarbonate, calcium carbonate, sodium hydroxide or potassium hydroxide;

Compound of Formula (VI) may be prepared by the reaction of a compoundof Formula (VIII)

and a compound of Formula (IX):R⁴—Y

L is a halogen atom (for example iodo or bromo) or a triflate group.

Y is a boronic acid, boronic ester or potassium trifluoroborate group(for example boronic acid, boronic acid pinacol ester, or potassiumtrifluoroborate)

The reaction may be performed under standard conditions well known tothose skilled in the art, for example in the presence of a palladiumsource and a phosphine ligand, (for example tetrakis(triphenylphosphine)palladium(0),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) also knownas Pd(dppf)Cl₂), and a suitable base (for example cesium carbonate orpotassium carbonate).

Compound of Formula (VIII) may be prepared by the reaction of a compoundof Formula (X) by reaction with ammonia (as described in Examples 2 and86)

L is a halogen atom (for example iodo or bromo) or a triflate group.

It is understood that a compound of Formula (VIII) may transformed intoanother compound of Formulae (VIII), for example as illustrated inExample 39 (preparation of 6-amino-4-chloronicotinonitrile).

Route D

Other compounds of Formula (I) may for example be prepared by thereaction of a compound of Formula (XI) with a compound of Formula (IX)R⁴—Y:

L is a halogen atom (for example iodo, bromo or chloro) or a triflategroup.

Y is a boronic acid, boronic ester or potassium trifluoroborate group(for example boronic acid, boronic acid pinacol ester, or potassiumtrifluoroborate)

The reaction may be performed under standard conditions well known tothose skilled in the art, for example in the presence of a palladiumsource and a phosphine ligand (for example: 2^(nd) Generation XPhosPrecatalyst also known aschloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II),or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)), and asuitable base (for example potassium phosphate or cesium carbonate).

Alternatively, Compounds of Formula (I) may for example be prepared bythe reaction of a compound of Formula (XI) with a compound of Formula(XII) R⁴—H, by a “C—H activation” reaction, as described in Example 7 or22.

Compound of Formula (XI) may be prepared by the reaction of a compoundof Formula (VIII)

L is a halogen atom (for example iodo, bromo or chloro) or a triflategroup.

with a compound of Formula (VII):

Suitable coupling agents for this reaction include for example,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, HATU, TBTU(2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouroniumtetrafluoroborate) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride ion, preferably 1-chloro-N,N,2-trimethylprop-1-en-1-amineand 1-propanephosphonic anhydride (T₃P).

The reaction is conveniently carried out in the presence of a suitablebase. A suitable base is, for example, an organic amine base such as,for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, N-methylmorpholine, diazabicyclo[5.4.0]undec-7-ene,diisopropylethyl amine, or, for example, an alkali or alkaline earthmetal carbonate or hydroxide, for example sodium carbonate, potassiumcarbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.It is understood that any compounds of Formulae (XI) can be transformedin another compound of Formulae (XI), for example by acylation of anamino group as in Example 39 or 75.

Route E

Some compounds of Formula (I) may for example be prepared by thereaction of a compound of Formula (XIII) with a compound of Formula (V)R⁴-L:

Y is a boronic acid, boronic ester or potassium trifluoroborate group(for example boronic acid, boronic acid pinacol ester, or potassiumtrifluoroborate)

L is a halogen atom (for example iodo or bromo) or a triflate group.

The reaction may be performed under standard conditions well known tothose skilled in the art, for example in the presence of a palladiumsource and a phosphine ligand (for example tetrakis(triphenylphosphine)palladium(0),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) also knownas Pd(dppf)Cl₂, and a suitable base (for example cesium carbonate orpotassium phosphate).

Compounds of Formula (XIII) may for example be prepared by the reactionof a compound of Formula (XI), as described in Example 16.

Route F

Some compounds of Formula (I) may for example be prepared by a“cyclisation” reaction of a compound of Formula (XV):

where R⁴⁰ is

wherein X¹ and Y¹ are defined such as (XV) is the precursor in thecyclisation reaction, with the proviso that X¹ and Y¹ together with theatoms to which they are attached do not form a ring. For example, X¹ orY¹ can be hydrogen.

The “cyclisation” reaction may be performed under standard conditionswell known to those skilled in the art. As an illustration, Examples 78and 82 describe a particular example of such a “cyclisation” reaction.

Compounds of Formula (XV) may be obtained by analogous routes to routesA to E described for making compounds of Formula (I). As an example, byanalogy with route D, compounds of Formula (XV) may be prepared by thereaction of a compound of Formula (XI) with a compound of Formula (XVI):R⁴⁰—Y:

L is a halogen atom (for example iodo, bromo or chloro) or a triflategroup.

Y is a boronic acid, boronic ester or potassium trifluoroborate group(for example boronic acid, boronic acid pinacol ester, or potassiumtrifluoroborate)

Alternatively, Compounds of Formula (XV) may for example be prepared bythe reaction of a compound of Formula (XI) with a compound of Formula(XVII) R⁴⁰—H, by a “C—H activation” reaction.

The reaction may be performed under standard conditions well known tothose skilled in the art, as described in Route D

Compounds of formula (IX) R₄—Y, where Y is a boronic acid, boronic esteror potassium trifluoroborate group (for example boronic acid, boronicacid pinacol ester, or potassium trifluoroborate), are key intermediatesin some of synthetic routes towards compound of formula (I).

Methods to synthetise a compound of formula (IX) from compound offormula (V) R₄-L, where L is a halogen atom (for example iodo, bromo orchloro) or a triflate group, include metallation/borylation reactions,as illustrated by Example 23 and 85, and palladium-catalysedborylations, as illustrated by Example 14.

Compound of formula (V) R₄-L are typically accessed from compound offormula (XII) R₄—H, by a halogenation reaction.

Compounds of formula (IX) R₄—Y, where Y is a boronic acid, boronic esteror potassium trifluoroborate group (for example boronic acid, boronicacid pinacol ester, or potassium trifluoroborate) may also be accesseddirectly from compounds of formula (XII) R₄—H, by a ‘C—H activation’reaction, as illustrated in Example 49. Typical conditions use aniridium catalyst (typically methoxy(cyclooctadiene)iridium(I) dimer) anda ligand (typically 4,4′-di-tert-butyl-2,2′-dipyridyl or3,4,7,8-tetramethyl-1,10-phenanthroline) with a source of boron(typically 4,4,5,5-tetramethyl-1,3,2-dioxaborolane) in an inert solvent(typically THF or dioxane) at around 50° C. to 90° C.

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminum trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminum trichloride) under Friedel Craftsconditions; and the introduction of a halogen group. Particular examplesof modifications include the reduction of a nitro group to an aminogroup by for example, catalytic hydrogenation with a nickel catalyst ortreatment with iron in the presence of hydrochloric acid with heating;oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T.W. Green, Protective Groups inOrganic Synthesis, John Wiley and Sons, 1991). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ortert-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a tert-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a tert-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of Formula (I), ora pharmaceutically acceptable salt thereof, as defined herein inassociation with a pharmaceutically acceptable diluent or carrier.

It is understood that a compound of Formula (I) can be obtained byseparation (e.g. chiral separation) from a mixture of compounds ofFormula (I); for Examples 9 and 2, 41 and 42, 43 and 14, 59 and 60, 61and 62, 64 and 65, 68 and 69, 70 and 71, 72 and 73, 79 and 80, 83 and84.

Some compounds of Formulae (II), (V), (VI), (IX), (XI), (XII), (XIII),(XV), (XVI) and (XVII) are novel.

(1S,3R)-3-(acetamino)cyclohexanecarboxylic acid is a key intermediate inthe synthesis of some compounds of Formula (I). The following route(schematic below, described in Example 85), giving access to this keyintermediate in an enantiomerically pure form, is novel and useful.

(1S,3R)-3-(acetamino)cyclohexanecarboxylic acid

This route is based on the enzymatic enantioselective acylation ofisopropyl 3-aminocyclohexylcarboxylate (using Novozym 435) asillustrated below:

EXAMPLES

Aspects of the present disclosure can be further defined by reference tothe following non-limiting examples, which describe in detailpreparation of certain compounds and intermediates of the presentdisclosure and methods for using compounds of the present disclosure. Itwill be apparent to those skilled in the art that many modifications,both to materials and methods, can be practiced without departing fromthe scope of the present disclosure.

Unless stated othewise:

-   -   (i) operations were carried out at ambient temperature, i.e. in        the range 17 to 25° C. and under an atmosphere of an inert gas        such as nitrogen unless otherwise stated;    -   (ii) evaporations were carried out by rotary evaporation or        utilising Genevac equipment or a Biotage v10 evaporator in vacuo        and work-up procedures were carried out after removal of        residual solids by filtration;    -   (iii) flash chromatography purifications were performed on an        automated Teledyne Isco CombiFlash® Rf or Teledyne Isco        CombiFlash® Companion® using prepacked RediSep Rf Gold™ Silica        Columns (20-40 μm, spherical particles), GraceResolvy™        Cartridges (Davisil® silica) or Silicycle cartridges (40-63 μm).    -   (iv) preparative chromatography was performed on a Gilson prep        HPLC instrument with UV collection; alternatively, preparative        chromatography was performed on a Waters AutoPurification        HPLC-MS instrument with MS- and UV-triggered collection;    -   (v) chiral preparative chromatography was performed on a Gilson        instrument with UV collection (233 injector/fraction collector,        333 & 334 pumps, 155 UV detector) or a Varian Prep Star        instrument (2×SD1 pumps, 325 UV detector, 701 fraction        collector) pump running with Gilson 305 injection;        alternatively, chiral preparative chromatography was performed        on a Waters Prep 100 SFC-MS instrument with MS- and UV-triggered        collection or a Thar MultiGram III SFC instrument with UV        collection.    -   (vi) yields, where present, are not necessarily the maximum        attainable;    -   (vii) in general, the structures of end-products of the Formula        I were confirmed by nuclear magnetic resonance (NMR)        spectroscopy; NMR chemical shift values were measured on the        delta scale [proton magnetic resonance spectra were determined        using a Bruker Avance 500 (500 MHz) or Bruker Avance 400 (400        MHz) instrument]; measurements were taken at ambient temperature        unless otherwise specified; the following abbreviations have        been used: s, singlet; d, doublet; t, triplet; q, quartet; m,        multiplet; dd, doublet of doublets; ddd, doublet of doublet of        doublet; dq, double of quartets; dt, doublet of triplets; tt,        triplet of triplets; p, pentet; br, broad signal.    -   (viii) in general, end-products of the Formula I were also        characterised by mass spectroscopy following liquid        chromatography (LCMS or UPLC); UPLC was carried out using a        Waters UPLC fitted with Waters SQ mass spectrometer (Column temp        40, UV=220-300 nm, Mass Spec=ESI with positive/negative        switching) at a flow rate of 1 mL/min using a solvent system of        97% A+3% B to 3% A to 97% B over 1.50 min (total runtime with        equilibration back to starting conditions etc 1.70 min), where        A=0.1% formic acid in water (for acid work) or 0.1% ammonia in        water (for base work) B=acetonitrile. For acid analysis the        column used was Waters Acquity HSS T3 1.8 μm 2.1×50 mm, for base        analysis the column used was Waters Acquity BEH 1.7 μm        2.1×50 mm. Alternatively, UPLC was carried out using a Waters        UPLC fitted with a Waters SQ mass spectrometer (Column temp 30,        UV=210-400 nm, Mass Spec=ESI with positive/negative switching)        at a flow rate of 1 mL/min using a solvent gradient of 2 to 98%        B over 1.5 mins (total runtime with equilibration back to        starting conditions: 2 min), where A=0.1% formic acid in water        and B=0.1% formic acid in acetonitrile (for acid work) or A=0.1%        ammonium hydroxide in water and B=acetonitrile (for base work).        For acid analysis the column used was a Waters Acquity HSS T3        1.8 μm 2.1×30 mm, for base analysis the column used was a Waters        Acquity BEH C18 1.7 μm 2.1×30 mm; LCMS was carried out using a        Waters Alliance HT (2795) fitted with a Waters ZQ ESCi mass        spectrometer and a Phenomenex Gemini-NX (5 μm×2.1 mm) column at        a flow rate of 1.1 mL/min 95% A to 95% B over 4 min with a 0.5        min hold. The modifier was kept at a constant 5% C (50:50        acetonitrile:water 0.1% formic acid) or D (50:50        acetonitrile:water 0.1% ammonium hydroxide depending on whether        it was an acidic or basic method. It is understood that, unless        specified otherwise, only the most characteristic mass peak is        reported, rounded to the lower unit. Typically, when several        isotopes of one atom exist, only the lower most common isotope        is reported (e.g. ³⁵Cl, ⁷⁹Br, ¹²C . . . )    -   (ix) ion exchange purification was generally performed using an        SCX-2 (Biotage) cartridge.    -   (x) intermediate purity was assessed by thin layer        chromatographic, mass spectral, HPLC (high performance liquid        chromatography) and/or NMR analysis;    -   (xi) Optical rotation is measured in degrees;    -   (xii) XRPD analysis was performed using a Bruker D4        diffractometer, which is commercially available from Bruker AXS        Inc.™ (Madison, Wis.). The XRPD spectra were obtained by        mounting a sample (approximately 20 mg) of the material for        analysis on a single silicon crystal wafer mount (e.g., a Bruker        silicon zero background X-ray diffraction sample holder) and        spreading out the sample into a thin layer with the aid of a        microscope slide. The sample was spun at 30 revolutions per        minute (to improve counting statistics) and irradiated with        X-rays generated by a copper long-fine focus tube operated at 40        kV and 40 mA with a wavelength of 1.5406 angstroms (i.e., about        1.54 angstroms). The sample was exposed for 1 second per 0.02        degree 2-theta increment (continuous scan mode) over the range 2        degrees to 40 degrees 2-theta in theta-theta mode. The running        time was 31 min, 41 s. The skilled person appreciates that XRPD        20 values may vary with a reasonable range, e.g., in the range        ±0.1°2θ. The skilled person appreciates that XRPD intensities        may vary when measured for essentially the same crystalline form        for a variety of reasons including, for example, preferred        orientation. Principles of XRPD are described in publications,        such as, for example, Giacovazzo, C. et al. (1995), Fundamentals        of Crystallography, Oxford University Press; Jenkins, R. and        Snyder, R. L. (1996), Introduction to X-Ray Powder        Diffractometry, John Wiley & Sons, New York; and Klug, H. P. &        Alexander, L. E. (1974), X-ray Diffraction Procedures, John        Wiley and Sons, New York. Because the relative intensities are        less reliable and instead of numerical values the following        definitions are used.

% Relative Intensity Definition  25-100 vs (very strong) 10-25 s(strong)  3-10 m (medium) 1-3 w (weak) <1 vw (very weak)Some additional very weak peaks found in the diffractogram have beenomitted.

-   -   (xiii) DSC was performed using a TA Instruments model Q1000. A        sample (approximately 2 mg) was weighed into an aluminium sample        pan and transferred to the DSC. The instrument was purged with        nitrogen at 50 mL/min and data collected between 25° C. and 300°        C., using a dynamic heating rate of 10° C./min. DSC analysis was        performed on samples prepared according to standard methods        using a Q SERIES™ Q1000 DSC calorimeter available from TA        INSTRUMENTS® (New Castle, Del.). The instrument was purged with        nitrogen at 50 mL/min and data collected between 25° C. and 300°        C., using a dynamic heating rate of 10° C./minute. Thermal data        was analyzed using standard software, e.g., Universal v.4.5A        from TA INSTRUMENTS®.    -   (xiv) Thermogravimetry Analysis (TGA): TGA was performed using a        TA Instruments model Q5000. A sample (approximately 5 mg) was        placed into an aluminium sample pan and inserted to the TGA        furnace. The instrument was purged with nitrogen at 50 mL/min        and data collected between 25° C. and 300° C., using a dynamic        heating rate of 10° C./min. Thermal data are analyzed using        standard software, e.g., Universal v.4.5A from TA INSTRUMENTS®.    -   (xv) The following abbreviations have been used:        -   2^(nd) Generation XPhos (or X-Phos) Precatalyst            chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)            [2-(2′-amino-1,1′-biphenyl)]palladium(II)        -   3^(rd) Generation RuPhos Precatalyst            (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)            [2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate    -   aq. aqueous    -   atm atmosphere    -   BuLi n-butyl lithium    -   CDCl₃ deutero-chloroform    -   CD₃OD deutero-methanol    -   CDI carbonyl diimidazole    -   Conc. concentrated    -   DCM dichloromethane    -   DIPEA N,N-diisopropylethylamine    -   DMA N,N-dimethylacetamide    -   DMF N,N-dimethylformamide    -   DMSO dimethyl sulphoxide    -   DMSO-d₆ deutero-dimethyl sulphoxide    -   dppf 1,1′-bis(diphenylphosphino)ferrocene    -   DSC differential scanning calorimetry    -   EtOH ethanol    -   EtOAc ethyl acetate    -   HATU        1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxid hexafluorophosphate    -   h hour(s)    -   IPA/iPrOH isopropyl alcohol    -   MeCN acetonitrile    -   MeOH methanol    -   MTBE methyl-tert-butyl ether    -   NBS N-bromosuccinimide    -   NIS N-iodosuccinimide    -   NMP N-methylpyrrolidine    -   PdCl₂(dppf)        [1,1′-Bis(diphenylphosphinio)ferrocene]-dichloropalladium(II)    -   Pd(P(Cy)₃)₂Cl₂ Bis(tricyclohexylphosphine)dichloropalladium(II)    -   r.t. room temperature    -   SCX/SCX-2 strong cation exchange chromatography    -   SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride    -   SFC supercritical fluid chromatography    -   T₃P® propane phosphonic acid anhydride    -   TBS/TBDMS tert-butyldimethylsilyl    -   TBS-Cl tert-butyldimethylsilyl chloride    -   TEA triethylamine    -   TFA trifluoroacetic acid    -   TGA thermogravimetry analysis    -   THF tetrahydrofuran    -   TMEDA tetramethylethylenediamine    -   Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene    -   XRPD X-ray powder diffraction

Example 1:(R)—N-(5-chloro-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)piperidine-3-carboxamide

TFA (2 mL, 26.0 mmol) was added dropwise to (R)-tert-butyl3-((5-chloro-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)piperidine-1-carboxylate(0.40 g, 0.52 mmol) in DCM (5 mL). The resulting mixture was stirred atr.t. for 1 h before being concentrated under reduced pressure. Theresulting crude product was purified by preparative HPLC (Waters XBridgePrep C18 OBD column, 5 μm silica, 30 mm diameter, 100 mm length) usingdecreasingly polar mixtures of water (containing 0.1% ammoniumcarbonate) and MeCN as eluents. Fractions containing the desiredcompound were concentrated to dryness to afford(R)—N-(5-chloro-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)piperidine-3-carboxamide(22.0 mg, 11.7%) as a white solid. ¹H NMR (400 MHz, CD₃OD, 22° C.)1.41-1.52 (1H, m), 1.57-1.68 (2H, m), 1.85-1.94 (5H, m), 2.48-2.57 (2H,m), 2.68-2.76 (1H, m), 2.80-2.89 (3H, m), 2.97-3.03 (1H, m), 3.78-3.84(2H, m), 7.04 (1H, s), 8.10 (1H, s), 8.29 (1H, s), amide and piperidineNH's not observed. m/z: ES+ [M+H]+ 360.

Procedures for preparing the starting material (R)-tert-butyl3-((5-chloro-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)piperidine-1-carboxylateare described below:

Preparation of3-(2,5-dichloropyridin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine

Cesium carbonate (3.24 g, 9.95 mmol) was added to3-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (500 mg, 2.49 mmol),(2,5-dichloropyridin-4-yl)boronic acid (3.34 g, 17.4 mmol)Pd(dppf)Cl₂.CH₂Cl₂ (203 mg, 0.25 mmol), dioxane (10 mL), and water (1mL) under nitrogen. The resulting mixture was stirred at 90° C. for 2 h.The reaction mixture was concentrated under reduced pressure to drynessand redissolved in EtOAc (50 mL) before being washed sequentially withwater (2×20 mL) and saturated aqueous sodium chloride (50 mL). Theorganic layer was dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The resulting crude product was purified byflash silica chromatography, elution gradient 0 to 25% EtOAc inpetroleum ether. Pure fractions were concentrated to dryness to afford3-(2,5-dichloropyridin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine(500 mg, 75.0%) as a brown solid. m/z: ES+ [M+H]+ 268.

Preparation of (R)-tert-butyl3-((5-chloro-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)piperidine-1-carboxylate

3-(2,5-Dichloropyridin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine(460 mg, 1.72 mmol) was added to (R)-tert-butyl3-carbamoylpiperidine-1-carboxylate (470 mg, 2.06 mmol), Pd(PPh₃)₄ (198mg, 0.17 mmol), cesium carbonate (1.68 g, 5.15 mmol), Xantphos (199 mg,0.34 mmol), and dioxane (8 mL) under nitrogen. The resulting mixture wasstirred at 120° C. for 2 h. The reaction mixture was then filtered, andthe resulting filtrate was purified by flash silica chromatography,elution gradient 0 to 50% EtOAc in petroleum ether. Pure fractions wereconcentrated under reduced pressure to afford(R)-tert-butyl-3-((5-chloro-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-yl)pyridin-2-yl)carbamoyl)piperidine-1-carboxylate(400 mg, 50.7%) as a yellow oil. m/z: ES+ [M+H]+ 460.

Example 2:(1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Acetyl chloride (1.0 mL, 14.5 mmol) was added dropwise to a mixture of(1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(2.46 g, 6.59 mmol) and pyridine (6.40 mL, 79.1 mmol) in DCM (58.5 mL)at 0° C. After 45 min the mixture was washed with saturated aqueoussodium hydrogencarbonate and saturated aqueous sodium chloride beforebeing dried over sodium sulfate, filtered, and concentrated underreduced pressure. The resulting dark amber oil was purified by flashsilica chromatography, elution gradient 0 to 10% methanol in DCM.Product fractions were concentrated under reduced pressure to afford(1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(2.6 g, 93% yield over three steps) as a light beige foam solid.

Analysis of(1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamideby analytical SFC conditions (see below), determined this material tocontain 98%(1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(R_(t)=1.42 min) and 2% (1R,3S)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(R_(t)=2.42 min). This material was purified by preparative SFCconditions (Chiralpak IA column, 5 μm, 30 mm diameter, 250 mm length,40° C. column temperature, 100 bar outlet pressure, 120 mL/min flowrate), eluting with 40% methanol containing 0.1% dimethylethylamine inCO₂, to remove the (1R, 3S) enantiomer. Product fractions for the fastereluting enantiomer were concentrated under reduced pressure to afford2.3 g of an amber-pink solid. This solid was repurified by flash silica(plug) chromatography, elution gradient 0 to 10% MeOH in ethyl acetate,to afford(1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(2.25 g) as a white foam solid. The product was treated with 20 mL ofacetonitrile and the resulting mixture was warmed to reflux conditionsbefore being allowed to cool to r.t. Additional acetonitrile (˜5 mL) wasadded and the process was repeated until all solid dissolved. Theresulting faint yellow solution was cooled to r.t., and a precipitateformed. After 1 h the precipitate was filtered and washed withacetonitrile before being dried under vacuum at 65° C. for 1 h. Thesolid was cooled to r.t. to afford(1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(1.76 g). ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 0.97-1.17 (1H, m), 1.20-1.38(3H, m), 1.68-1.94 (9H, m), 1.96-2.07 (2H, m), 2.54-2.68 (1H, m), 2.80(2H, t), 3.46-3.65 (1H, m), 4.14 (2H, t), 7.73 (1H, d), 7.76 (1H, s),8.14 (1H, s), 8.38 (1H, s), 10.57 (1H, s). m/z: ES+ [M+H]+ 416.

Analytical SFC Conditions:

Column: Chiralpak IA column,

Column Dimensions: 5 μm, 4.6 mm diameter, 100 mm length,

Column Temperature: 40° C.

Mobile Phase A: CO₂ (100%)

Mobile Phase B: Methanol containing 0.1% dimethylethylamine

Gradient: Isocratic 40% Mobile Phase B

Outlet Pressure: 100 bar

Flow Rate: 5 mL/min over 5 min

Retention Time: 1.42 min

e.e. >98%

Optical Rotation:

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 25° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: Methanol

[α]=+70.2

The crystals of Example 2 were analyzed by XRPD and the results aretabulated below and are shown in FIG. 7. The XRPD of the solid confirmsthat the solid contains Example 2 Form B. Example 2 Form B main peaksare shown in Table 1 below:

Peak 2θ Intensity % 1 21.2 100.0 (vs)  2 27.4 88.7 (vs) 3 20.5 76.4 (vs)4 13.6 74.4 (vs) 5 21.6 58.1 (vs) 6 5.5 45.7 (vs) 7 26.7 43.8 (vs) 816.1 41.4 (vs) 9 6.8 37.0 (vs) 10 22.8 35.3 (vs)

According to the present invention there is provided a crystalline form,Form B, which has an X-ray powder diffraction pattern with specificpeaks at about 2-theta=5.5, 6.8, 13.6, 16.1, 20.5, 21.2, 21.6, 22.8,26.7, 27.4°.

The crystals obtained from Example 2 (Form B) were analyzed by thermaltechniques. DSC analysis indicated that Form B has several thermalevents, including an exotherm event with an onset point at 150° C. and apeak at 153° C., followed by melting with an onset point at 201° C. anda peak at 202° C. TGA indicated that Form B exhibits a mass loss ofabout 4.5% upon heating from 22° C. to 150° C. A representative DSC/TGAthermogram is shown in FIG. 8.

Procedures for preparing the starting material(1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of 5-chloro-4-iodopyridin-2-amine

The reaction was split into 4 separate sealed microwave reactionvessels, each containing 750 mg (2.95 mmol) of5-chloro-2-fluoro-4-iodopyridine, 8.4 mL of concentrated aqueousammonium hydroxide, and 7.5 mL of NMP. The reaction vessels were eachheated at 100° C. for 17 h. The combined batches were then diluted withwater (50 mL) and extracted with EtOAc (3×120 mL). The combined organiclayers were dried over MgSO₄, filtered, and concentrated under reducedpressure to afford a pale yellow oil. The oil was loaded onto a 20 gSCX-2 column and eluted sequentially with DCM, MeOH and 1% NH₃ in MeOH.Basic fractions were concentrated to provide the desired product as acolourless solid (2.9 g, 99%). ¹H NMR (400 MHz, DMSO-d₆, 30° C.) 6.21(2H, s), 7.05 (1H, s), 7.93 (1H, s). m/z: ES+ [M+H]+ 255.

Preparation of5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine

Cesium carbonate (13.4 g, 41.2 mmol) and PdCl₂(dppf).CH₂Cl₂ (0.94 g, 1.2mmol) were added sequentially to a degassed mixture of5-chloro-4-iodopyridin-2-amine (4.19 g, 16.5 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo-[1,5-a]pyridine(5.72 g, 23.1 mmol), 1,4-dioxane (141 mL) and water (23.5 mL). Theresulting red mixture was warmed to 95° C. and became clear. Withvigorous stirring some precipitate formed which gradually mostlyredissolved. After 4 h, another 800 mg of boronic ester were added;after another 40 min the reaction was cooled to r.t. and stirred underthese conditions for 18 h. The mixture was then diluted with ethylacetate, and the layers were separated. The organic layer was washedwith saturated aqueous sodium chloride, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The resulting oil waspurified by flash silica chromatography, elution gradient 0 to 10%methanol in ethyl acetate. Product fractions were combined, concentratedunder reduced pressure, and the resulting residue was stirred vigorouslyin 1:1 DCM:hexane for 20 minutes. The mixture was then diluted withhexane and filtered with a hexane wash. The resulting solid was driedunder vacuum to afford5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine(2.79 g, 68.1%) as light orange-beige needles. ¹H NMR (300 MHz, DMSO-d₆,27° C.) 1.74-1.88 (2H, m), 1.96-2.06 (2H, m), 2.76 (2H, t), 4.12 (2H,t), 6.03 (2H, br. s), 6.43 (1H, s), 7.63 (1H, s), 7.94 (1H, s). m/z: ES+[M+H]+ 249.

Preparation of cis-3-(tert-butoxvycarbonylamino)cyclohexanecarboxylicacid

A 5 litre fixed vessel was charged with cis-3-aminocyclohexanecarboxylicacid (100 g, 698 mmol; purchased from TCI), water (900 mL), 1,4-dioxane(900 mL) and N-ethyl-N-isopropylpropan-2-amine (487 mL, 2793 mmol).After stirring at r.t. for 5 min, the mixture was cooled to 0° C.Di-tert-butyl dicarbonate (168 g, 768 mmol) was then added portionwiseto the reaction mixture, which was allowed to warm to r.t. after thefinal portion was added. The reaction mixture was then recooled to 0° C.and 2 M aqueous HCl was added to adjust the pH to 2. A small (<5° C.)exotherm was observed between the addition of each 50 mL portion of 2 Maqueous HCl. The reaction mixture was extracted with EtOAc (2×500 mL),and the combined organic layers were washed with water (400 mL) anddried over sodium sulfate. The mixture was filtered, and the filtratewas concentrated under reduced pressure to afford, upon dryingovernight, cis-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid(170 g, 100%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.)0.95-1.33 (4H, m), 1.37 (9H, s), 1.64-1.75 (2H, m), 1.79 (1H, d), 1.94(1H, d), 2.22 (1H, tt), 3.13-3.26 (1H, m), 6.72 (1H, d), 12.01 (1H, s).m/z: ES+ [M+Na]+ 266.

Preparation of (S)-1-phenylethanaminium(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate

Using a procedure similar to that described in WO2011/1106112,cis-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (49.9 g,166 mmol) was added to a 1 L round bottom flask and dissolved in ethanol(400 mL). The mixture was stirred at r.t. until all starting materialdissolved. (S)-1-phenylethanamine (23.6 mL, 183 mmol) was added; themixture was stirred at r.t. until a white precipitate gradually formed.The reaction mixture was then heated to 80° C. until a clear solutionwas obtained. The reaction heater was then switched off, and thereaction mixture was allowed to cool to r.t. After stirring at r.t. foranother 16 h, the resulting mixture was filtered to give a white solid.This solid was re-dissolved in ethanol (150 mL) and heated to 80° C.until a clear solution was obtained. The reaction heater was thenswitched off, and the reaction mixture was allowed to cool to r.t.Filtration afforded a white solid (14.6 g), which was againrecrystallized from ethanol (100 mL) using the same procedure to afford(S)-1-phenylethanaminium(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate (12.5 g,20.7%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.) 0.98-1.23(4H, m), 1.26 (3H, d), 1.38 (9H, s), 1.66-1.84 (3H, m), 1.95 (1H, m),2.21 (1H, m), 3.21 (1H, m), 4.00 (1H, q), 6.72 (1H, m), 7.16-7.23 (1H,m), 7.30 (2H, m), 7.34-7.4 (2H, m), NH₃ ⁺ not observed.

Preparation of (1S,3R)-3-(tert-butoxycarbonylamino)cyclohexanecarboxylicacid

(S)-1-phenylethanaminium(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexane-carboxylate (9.85 g,27.0 mmol) was suspended in 250 mL EtOAc, and the organic layer waswashed with 0.5 M HCl (2×125 mL). The organic layer was collected, andthe combined aqueous layers were extracted with EtOAc (300 mL). Thecombined organic layers were washed with water (2×500 mL) and saturatedaqueous sodium chloride (500 mL) before being dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The resulting solidwas then dried under vacuum to afford(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (5.5 g,84%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.) 0.99-1.35 (4H,m), 1.38 (9H, s), 1.68-1.85 (3H, m), 1.96 (1H, d), 2.23 (1H, tt),3.15-3.30 (1H, m, partially obscured by water peak), 6.72 (1H, d), 12.01(1H, s).

Representative Determination of Enantiopurity:

HATU (0.413 g, 1.09 mmol) was added to a solution of(4-methoxyphenyl)methanamine (0.142 mL, 1.09 mmol),(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (0.240g, 0.99 mmol), DIPEA (0.345 mL, 1.97 mmol), and DMF (1.980 mL). Thebright yellow solution became a mixture over 30 min and was then dilutedwith ethyl acetate and sequentially washed with water, saturated aqueoussodium bicarbonate, and saturated aqueous sodium chloride. The organiclayer was then dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The resulting residue was purified by flashsilica chromatography, eluting with isocratic 5% methanol in DCM, toafford tert-butyl((1R,3S)-3-((4-methoxybenzyl)carbamoyl)cyclohexyl)carbamate (0.30 g,84%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 0.97-1.14 (1H,m), 1.15-1.32 (3H, m), 1.38 (9H, s), 1.56-1.84 (4H, m), 2.12-2.29 (1H,m), 3.14-3.28 (1H, m), 3.73 (3H, s), 4.17 (2H, br. d), 6.70-6.77 (1H,m), 6.87 (2H, d), 7.14 (2H, d), 8.16 (1H, t). m/z: ES+ [M+H]+ 363.

Samples prepared in this manner were subsequently analyzed by analyticalSFC conditions as follows:

Column: Chiralpak OD column,

Column Dimensions: 5 μm, 4.6 mm diameter, 250 mm length,

Column Temperature: 40° C.

Mobile Phase A: CO₂ (100%)

Mobile Phase B: Ethanol

Gradient: Isocratic 15% Mobile Phase B

Outlet Pressure: 100 bar

Flow Rate: 2.8 mL/min over 5 min

Retention Time(s):

3.33 min, tert-butyl((1R,3S)-3-((4-methoxybenzyl)carbamoyl)cyclohexyl)carbamate

5.21 min, tert-butyl((1S,3R)-3-((4-methoxybenzyl)carbamoyl)cyclohexyl)carbamate

Preparation of tert-butyl((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(Also Known as Example 31a)

1-Chloro-N,N,2-trimethylprop-1-en-1-amine (1.12 mL, 8.44 mmol) was addedto a solution of(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (2.01g, 8.24 mmol) in DCM (50 mL) at 0° C. The reaction was maintained underthese conditions for 100 minutes. During this time,5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine(1.64 g, 6.59 mmol), pyridine (2.1 mL, 26.4 mmol) and DCM (20 mL) werecombined in a separate flask. The resulting mixture was warmed gently(˜40° C.) until all solids dissolved. The resulting solution was thencooled to 0° C., whereupon a homogeneous light yellow mixture formed.This mixture was added via cannula rapidly to the previously preparedsolution of (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylicacid and 1-chloro-N,N,2-trimethylprop-1-en-1-amine, resulting in adarker yellow solution. The reaction was allowed to warm to r.t.overnight and was then evaporated to dryness. The gray mixture was thentaken on to the next step without further purification. m/z: ES+ [M+H]+474.

Preparation of(1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamidedihydrochloride (Also Known as Example 31b)

Hydrochloric acid in dioxane (4 M; 10 mL, 40 mmol) was added to amixture of crude tert-butyl((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(3.12 g, 6.59 mmol) in DCM (5 mL) and methanol (5 mL) at 0° C. Themixture became an amber solution. After 1 h the amber solution wasconcentrated under reduced pressure, and the resulting residue was driedunder vacuum to a beige/gray foam solid. This material was carried on tothe next step without further purification. m/z: ES+ [M+H]+ 374.

Example 3:(1S,3R)-3-acetamido-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Acetic anhydride (0.016 mL, 0.17 mmol) was added to(1S,3R)-3-amino-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(47 mg, 0.14 mmol) and triethylamine (0.023 mL, 0.17 mmol) in DCM (1 mL)at 21° C. under nitrogen. The resulting solution was stirred under theseconditions for 60 h. The reaction mixture was loaded directly ontosilica and purified by flash silica chromatography, elution gradient 1to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford(1S,3R)-3-acetamido-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(43 mg, 81%) as a white solid. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.07-1.23(1H, m), 1.37-1.53 (3H, m), 1.87-2.03 (8H, m), 2.03-2.11 (2H, m), 2.25(1H, d), 2.39-2.51 (1H, m), 3.06 (2H, t), 3.88 (1H, dtq), 4.20 (2H, t),5.40 (1H, d), 7.10 (1H, dd), 7.80 (1H, s), 8.17 (1H, dd), 8.32 (1H, s),8.35 (1H, s). m/z: ES+ [M+H]+ 382.

Procedures for preparing the starting material(1S,3R)-3-amino-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of tert-butyl((1R,3S)-3-((4-bromopyridin-2-yl)carbamoyl)cyclohexyl)carbamate

1-Chloro-N,N,2-trimethylprop-1-en-1-amine (0.574 ml, 4.33 mmol) wasadded to a solution of(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (1.01g, 4.16 mmol; prepared according to Example 2) in DCM (40 ml) at 0° C.After 1.5 h, a mixture of 4-bromopyridin-2-amine (0.6 g, 3.47 mmol) andpyridine (1.12 ml, 13.9 mmol) in DCM (33.0 ml) was added via cannula.The resulting yellow mixture was allowed to warm to r.t. and was stirredunder these conditions for 72 h. The now white mixture was filtered,rinsed with a cold DCM wash, and the white precipitate was dried undervacuum at 70° C. for 30 min to afford tert-butyl((1R,3S)-3-((4-bromopyridin-2-yl)carbamoyl)cyclohexyl)carbamate (1.38 g,100%) of 95% purity as a white solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)0.99-1.35 (4H, m) 1.38 (9H, s) 1.68-1.80 (3H, m) 1.88 (1H, d) 2.53-2.64(1H, m) 3.15-3.35 (1H, m) 6.76 (1H, d) 7.34 (1H, dd) 8.21 (1H, d) 8.33(1H, d) 10.63 (1H, s). m/z: ES+ [M+H]+ 398.

Preparation of tert-butyl((1R,3S)-3-((4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate

2nd Generation XPhos Precatalyst (9.88 mg, 0.01 mmol) was added in oneportion to a degassed mixture of tert-butyl((1R,3S)-3-((4-bromopyridin-2-yl)carbamoyl)cyclohexyl)carbamate (100 mg,0.25 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(93 mg, 0.38 mmol), potassium phosphate (160 mg, 0.75 mmol), 1,4-dioxane(2 mL), and water (0.2 mL) at 21° C. under nitrogen. The resultingmixture was stirred at 100° C. for 16 h. The reaction mixture wasdiluted with EtOAc (10 mL), and washed sequentially with saturatedNaHCO₃ (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL),and the combined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford crude product. The crudeproduct was purified by flash silica chromatography, elution gradient 20to 80% EtOAc in heptane. Pure fractions were evaporated to dryness toafford tert-butyl((1R,3S)-3-((4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(70.0 mg, 63.4%) as a white powder. ¹H NMR (400 MHz, DMSO-d₆, 30° C.)1.12 (1H, d), 1.21-1.33 (3H, m), 1.39 (9H, s), 1.76 (3H, s), 1.82-1.95(3H, m), 2.00 (2H, d), 2.59 (1H, s), 2.97 (2H, t), 3.89 (1H, s), 4.12(2H, t), 6.75 (1H, s), 7.19 (1H, dd), 7.85 (1H, s), 8.22 (2H, d), 10.32(1H, s). m/z: ES+ [M+H]+ 440.

Preparation of(1S,3R)-3-amino-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

HCl in dioxane (4 M; 0.199 mL, 0.80 mmol) was added dropwise totert-butyl((1R,3S)-3-((4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(70 mg, 0.16 mmol) in DCM (2 mL) at 21° C. under nitrogen. The resultingmixture was stirred at 21° C. for 16 h. MeOH (1 mL) was added, and themixture was purified directly by ion exchange chromatography, using anSCX-2 column. The desired product was eluted using 1 M NH₃ in MeOH, andpure fractions were evaporated to dryness to afford(1S,3R)-3-amino-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(47 mg, 87%) as a white crystalline solid. ¹H NMR (400 MHz, CD₃OD, 30°C.) 0.95-1.08 (1H, m), 1.2-1.4 (3H, m), 1.76-1.91 (5H, m), 1.99 (3H,dtt), 2.44 (1H, ddd), 2.61 (1H, tt), 2.95 (2H, t), 3.25 (1H, s), 4.07(2H, t), 7.11 (1H, dd), 7.74 (1H, s), 8.07-8.16 (2H, m), NH₂ peak notobserved. m/z: ES+ [M+H]+ 340.

Example 4:Cis-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide

HCl in dioxane (4 M; 0.388 mL, 1.55 mmol) was added tocis-3-((tert-butyldimethylsilyl)oxy)-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclobutanecarboxamide(143 mg, 0.31 mmol) in DCM (3 mL) at 21° C. under nitrogen. Theresulting suspension was stirred at 21° C. for 30 minutes. MeOH (1 mL)was added and the mixture stirred at 21° C. for 16 h. The mixture wasconcentrated and then diluted with EtOAc (25 mL) and saturated aqueousNaHCO₃ (25 mL). The layers were separated, and the aqueous layer wasextracted with EtOAc (25 mL). The combined organic layers were driedover sodium sulfate and concentrated under reduced pressure. Theresulting crude product was purified by flash silica chromatography,elution gradient 50 to 100% EtOAc in heptane. Pure fractions wereevaporated to dryness to affordcis-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide(24.0 mg, 22.3%) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃, 30° C.)1.88-1.94 (2H, m), 2.05-2.15 (3H, m), 2.2-2.31 (2H, m), 2.62-2.73 (3H,m), 2.93 (2H, t), 4.18-4.31 (3H, m), 7.81 (1H, s), 7.88 (1H, s), 8.23(1H, s), 8.26 (1H, d). m/z: ES+ [M+H]+ 347.

Procedures for preparing the starting materialcis-3-((tert-butyldimethylsilyl)oxy)-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclobutanecarboxamideare described below:

Preparation of cis-tert-butyldimethylsilyl3-((tert-butyldimethylsilyl)oxy)cyclobutanecarboxylate

Cis-3-hydroxycyclobutanecarboxylic acid (300 mg, 2.58 mmol) wasdissolved in DCM (17.2 mL). Tert-butylchlorodimethylsilane (818 mg, 5.43mmol) and 1H-imidazole (369 mg, 5.43 mmol) were added sequentially, andthe solution was placed under nitrogen. The reaction was allowed to stirfor 16 h at r.t. The mixture was diluted with ethyl acetate (100 mL) andwashed with 1N aqueous HCl (30 mL), water (30 mL), and saturated aqueoussodium chloride (40 mL) before being dried over magnesium sulfate,filtered, and concentrated under reduced pressure to affordcis-tert-butyldimethylsilyl3-((tert-butyldimethylsilyl)oxy)cyclobutanecarboxylate (802 mg, 90%) asa white solid. ¹H NMR (400 MHz, CDCl₃, 30° C.) 0.03 (6H, s), 0.26 (6H,s), 0.88 (9H, s), 0.94 (9H, d), 2.11-2.21 (2H, m), 2.43-2.63 (3H, m),4.07-4.17 (1H, m).

Preparation of cis-3-((tert-butyldimethylsilyl)oxy)cyclobutanecarboxylicacid

Potassium carbonate (644 mg, 4.66 mmol) was added to a solution ofcis-tert-butyldimethylsilyl3-((tert-butyldimethylsilyl)oxy)cyclobutanecarboxylate (803 mg, 2.33mmol) in THF (15 mL) and water (3 mL). The resulting mixture was stirredat r.t. for 20 h. The reaction mixture was diluted with water and washedwith EtOAc. The aqueous layer was acidified with 0.1N aqueous HCl andextracted with EtOAc (×2). The combined organic layers were dried oversodium sulfate, filtered, and concentrated to give crude product whichwas used without purification in the next step. ¹H NMR (400 MHz, CDCl₃,30° C.) 0.00 (6H, s), 0.84 (9H, s), 2.09-2.29 (2H, m), 2.36-2.66 (3H,m), 3.97-4.23 (1H, m), CO₂H not observed.

Preparation of3-(5-chloro-2-fluoropyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine

3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(500 mg, 2.02 mmol), 5-chloro-2-fluoro-4-iodopyridine (432 mg, 1.68mmol), 2nd Generation XPhos Pre-catalyst (132 mg, 0.17 mmol) andpotassium phosphate (1069 mg, 5.03 mmol) were suspended in dioxane (5mL) and water (0.50 mL). The reaction was degassed by bubbling nitrogenthrough the reaction mixture for 5 minutes before being heated to 90° C.The reaction was maintained under these conditions for 20 h and thendiluted with water (20 mL) and EtOAc (20 mL). The layers were separatedand the aqueous layer was extracted with EtOAc (3×20 mL). The combinedorganic layers were washed with saturated aqueous sodium chloride (20mL), dried over MgSO₄, filtered, and concentrated under reducedpressure. The resulting crude product was purified by flash silicachromatography, elution gradient 20 to 80% EtOAc in heptane. Purefractions were evaporated to dryness to afford3-(5-chloro-2-fluoropyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(440 mg, 104%) as a cream-colored crystalline solid. This material wastaken on to the next step without further purification.

¹H NMR (400 MHz, CDCl₃, 30° C.) 1.87-1.96 (2H, m), 2.08-2.16 (2H, m),2.83 (2H, t), 4.23 (2H, t), 6.82 (1H, d), 7.80 (1H, s), 8.23 (1H, s).m/z: ES⁺ [M+H]⁺ 252.

Preparation of5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine

3-(5-Chloro-2-fluoropyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(440 mg, 1.49 mmol) and ammonium hydroxide (2.0 mL, 51 mmol) werecombined and sealed into a microwave tube. The reaction was heated to150° C. for 2 h in a microwave reactor and cooled to r.t. The reactionmixture was diluted with EtOAc (25 mL) and water (25 mL). The layerswere separated, and the aqueous layer was extracted with EtOAc (3×25mL). The organic layers were combined and washed with saturated aqueoussodium chloride (25 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The resulting crude product was purified byflash silica chromatography, eluting with 50% EtOAc in heptane and then10% MeOH in DCM. Pure fractions were evaporated to dryness to afford5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine(80 mg, 22%) as a white solid, already characterised (See Example 3,Intermediates)

Preparation ofcis-3-((tert-butyldimethylsilyl)oxy)-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclobutanecarboxamide

N-Ethyl-N-isopropylpropan-2-amine (0.167 mL, 0.94 mmol) was added tocis-3-((tert-butyldimethylsilyl)oxy)cyclobutanecarboxylic acid (79 mg,0.34 mmol) and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (179 mg, 0.47 mmol) in DMF (1 mL) at 21° C. undernitrogen. The resulting solution was stirred at 21° C. for 10 minutes. Asolution of5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine(78 mg, 0.31 mmol) in DMF (1 mL) was added and the resulting mixture wasstirred at 21° C. for 16 h. Stirring continued for 72 h and additionalcis-3-((tert-butyldimethylsilyl)oxy)cyclobutanecarboxylic acid (79 mg,0.34 mmol),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (179 mg, 0.47 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.167 mL, 0.94 mmol) were added. Themixture was stirred for a further 24 h before EtOAc (20 mL) andsaturated aqueous sodium hydrogencarbonate (20 mL) were added. Thelayers were separated, and the organic layer was washed with water (20mL) and saturated aqueous sodium chloride (20 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The crude residue wastaken immediately onto the next step and recovery was assumed to bequantitative. m/z: ES+ [M+H]+ 461.

Example 5:(R)—N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)piperidine-3-carboxamide

TFA (1 mL, 13 mmol) was added to (R)-tert-butyl3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)piperidine-1-carboxylate(90 mg, 0.20 mmol) in DCM (2 mL) at 20° C. The resulting mixture wasstirred at r.t. for 1 h and then concentrated under reduced pressure.The resulting crude product was purified by preparative HPLC (XBridgePrep C18 OBD column, 5 μm silica, 19 mm diameter, 150 mm length), usingdecreasingly polar mixtures of water (containing 0.05% NH₃) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness to afford(R)—N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)piperidine-3-carboxamide(18.0 mg, 25.6%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, 23° C.)1.30-1.47 (1H, m), 1.52-1.62 (2H, m), 1.76-1.90 (3H, m), 1.97-2.07 (2H,m), 2.52-2.62 (2H, m), 2.69 (1H, t), 2.75-2.87 (3H, m), 2.91-3.01 (1H,m), 4.14 (2H, t), 7.77 (1H, s), 8.15 (1H, s), 8.37 (1H, s), 10.84 (1H,s), piperidine NH not observed. m/z: ES+ [M+H]+ 360.

Procedures for preparing the starting material (R)-tert-butyl3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)piperidine-1-carboxylateare described below:

Preparation of tert-butyl3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)piperidine-1-carboxylate

Pyridine (0.10 mL, 1.3 mmol) was added to1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (74 mg, 0.32 mmol)and 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.050 mL, 0.64 mmol) inDCM (2 mL) at 20° C. The resulting mixture was stirred at r.t. for 20minutes. Then5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine(80 mg, 0.32 mmol; prepared according to Example 4) was added to themixture. The resulting mixture was stirred at r.t. for 1 h. The reactionmixture was concentrated under reduced pressure and diluted with DCM(100 mL) before being washed sequentially with 0.1 M HCl (2×25 mL),saturated aqueous sodium bicarbonate (25 mL), and saturated aqueoussodium chloride (2×25 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by preparative TLC (petroleum ether:EtOAc=10:1) toafford tert-butyl3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)piperidine-1-carboxylate (100 mg, 67.6%) as ayellow solid. m/z: ES+ [M+H]+ 460.

Example 6:cis-3-hydroxy-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclobutanecarboxamide

HCl in dioxane (4 M; 0.388 mL, 1.55 mmol) was added tocis-3-((tert-butyldimethylsilyl)oxy)-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclobutanecarboxamide(132 mg, 0.31 mmol) in DCM (3 mL) and MeOH (1 mL) at 21° C. undernitrogen. The resulting suspension was stirred at 21° C. for 3 h beforethe mixture was concentrated under reduced pressure. The resultingresidue was diluted with EtOAc (25 mL) and saturated aqueous sodiumhydrogencarbonate (25 mL). The layers were then separated, and theaqueous layer was extracted with EtOAc (25 mL). The combined organiclayers were dried over MgSO₄ and concentrated under reduced pressure.The resulting crude solid was triturated with Et₂O and dried undervacuum to affordcis-3-hydroxy-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclobutanecarboxamide(35.0 mg, 36.1%) as a white solid. ¹H NMR (400 MHz, CDCl₃, 30° C.)1.89-2.01 (2H, m), 2.08 (3H, ddd), 2.28 (2H, ddd), 2.67 (3H, tq), 3.08(2H, t), 4.23 (3H, dt), 7.10 (1H, dd), 7.81 (1H, s), 7.83 (1H, s), 8.19(1H, dd), 8.33 (1H, s). m/z: ES+ [M+H]+ 313.

Procedures for preparing the starting materialcis-3-((tert-butyldimethylsilyl)oxy)-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclobutanecarboxamideare described below:

Preparation ofcis-N-(4-bromopyridin-2-yl)-3-((tert-butyldimethylsilyl)oxy)cyclobutanecarboxamide

N-Ethyl-N-isopropylpropan-2-amine (0.461 mL, 2.60 mmol) was added tocis-3-((tert-butyldimethylsilyl)oxy)cyclobutanecarboxylic acid (220 mg,0.95 mmol; prepared as in Example 4) and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (494 mg, 1.30 mmol) in DMF (3 mL) at 21° C. undernitrogen. The resulting solution was stirred at 21° C. for 10 minutesbefore 4-bromopyridin-2-amine (150 mg, 0.87 mmol) was added, and theresulting mixture was stirred at 21° C. for 16 h. Stirring continued for72 h, and additionalcis-3-((tert-butyldimethylsilyl)oxy)cyclobutanecarboxylic acid (79 mg,0.34 mmol),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (179 mg, 0.47 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.167 mL, 0.94 mmol) were added. Themixture was stirred for a further 24 h, and then EtOAc (25 mL) andsaturated aqueous sodium hydrogencarbonate solution (25 mL) were added.The layers were separated, and the organic layer was washed with water(2×25 mL) and saturated aqueous sodium chloride (2×25 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The resultingcrude product was purified by flash silica chromatography, elutiongradient 0 to 100% EtOAc in heptane. Pure fractions were evaporated todryness to affordcis-N-(4-bromopyridin-2-yl)-3-((tert-butyldimethylsilyl)oxy)cyclobutanecarboxamide(96 mg, 29%) as a colourless oil. ¹H NMR (400 MHz, CDCl₃, 30° C.) 0.06(6H, s), 0.89 (9H, s), 1.11-1.18 (1H, m), 2.23-2.31 (2H, m), 2.54-2.58(2H, m), 4.15-4.26 (1H, m), 7.18 (1H, dd), 7.82 (1H, s), 8.06 (1H, dd),8.49 (1H, d). m/z: ES+ [M+H]+ 385 (⁷⁹Br isotope), 387 (⁸¹Br isotope).

Preparation ofcis-3-((tert-butyldimethylsilyl)oxy)-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclobutanecarboxamide

2nd Generation XPhos Precatalyst (19.40 mg, 0.02 mmol) was added to adegassed mixture ofcis-N-(4-bromopyridin-2-yl)-3-((tert-butyldimethylsilyl)oxy)cyclobutanecarboxamide(95 mg, 0.25 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(73.4 mg, 0.30 mmol) and potassium phosphate (157 mg, 0.74 mmol) indioxane (2 mL) and water (0.2 mL) at 21° C. under nitrogen. Theresulting mixture was stirred at 100° C. for 16 h. The reaction mixturewas diluted with EtOAc (25 mL) and washed sequentially with saturatedaqueous sodium hydrogencarbonate (10 mL), water (10 mL), and saturatedaqueous sodium chloride (10 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure. The resultingcrude product was purified by flash silica chromatography, elutiongradient 30 to 70% EtOAc in heptane. Pure fractions were evaporated todryness to affordcis-3-((tert-butyldimethylsilyl)oxy)-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclobutanecarboxamide(60.0 mg, 57.1%) as a white solid. ¹H NMR (400 MHz, CDCl₃, 30° C.) 0.05(6H, s), 0.89 (9H, s), 1.9-2.01 (2H, m), 2.02-2.12 (2H, m), 2.25-2.33(2H, m), 2.5-2.62 (3H, m), 3.08 (2H, t), 4.21 (3H, t), 7.09 (1H, dd),7.76 (1H, s), 7.80 (1H, s), 8.18 (1H, dd), 8.33 (1H, s). m/z: ES+ [M+H]+427.

Example 7:(1S,3R)-3-acetamido-N-(5-chloro-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

(1S,3R)-3-Acetamido-N-(4-bromo-5-chloropyridin-2-yl)cyclohexanecarboxamide(0.20 g, 0.53 mmol), 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (47 mg,0.38 mmol), cesium carbonate (0.14 g, 0.42 mmol), triethylamine (0.11mL, 0.76 mmol), triphenylphosphine (0.02 g, 0.06 mmol) anddiacetoxypalladium (6.85 mg, 0.0300 mmol) were suspended in 1,4-dioxane(5 mL) and sealed in a microwave tube. The reaction was heated to 100°C. for 16 h in a microwave reactor and then cooled to .r.t. The reactionwas concentrated under reduced pressure and the crude product waspurified by ion exchange chromatography using an SCX-2 column. Thedesired product was eluted from the column using 1 M NH₃ in MeOH, andpure fractions were evaporated to dryness. The resulting crude productwas purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μsilica, 50 mm diameter, 100 mm length), using decreasingly polarmixtures of water (containing 1% NH₃) and MeCN as eluents. Fractionscontaining the desired compound were concentrated under reduced pressureto afford(1S,3R)-3-acetamido-N-(5-chloro-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.069 g, 44%) as a yellow gum. 1H NMR (500 MHz, DMSO-d₆, 30° C.)0.95-1.16 (1H, m), 1.19-1.39 (3H, m), 1.78 (3H, s), 1.83-1.97 (2H, m),2.55-2.68 (1H, m), 2.84 (2H, s), 3.18 (2H, dd), 3.31 (3H, s), 3.57 (1H,dt), 3.83 (2H, s), 4.08 (1H, q), 7.13 (1H, s), 7.75 (1H, d), 8.16 (1H,s), 8.47 (1H, s), 10.70 (1H, s). m/z: ES+ [M+H]+ 417 (¹³C, ³⁵Cl isotopesecondary peak).

Procedures for preparing the starting material(1S,3R)-3-acetamido-N-(4-bromo-5-chloropyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of 4-bromo-3-chloropyridin-2-amine

N-Chloro-succinimide (3.70 g, 27.7 mmol) dissolved in DMF (20 mL) wasadded dropwise to 4-bromopyridin-2-amine (4.40 g, 25.4 mmol) in DMF (50mL) at −78° C. over a period of 30 minutes under nitrogen. The resultingsuspension was then allowed to warm to r.t. After stirring under theseconditions for 24 h, the reaction mixture was diluted with Et₂O (50 mL)and washed sequentially with 1 M aqueous NaOH (2×50 mL), water (50 mL),and saturated aqueous sodium chloride (25 mL). The organic layer wasdried over MgSO₄, filtered and concentrated under reduced pressure. Theresulting crude product was purified by flash silica chromatography,elution gradient 0 to 25% EtOAc in DCM. Pure fractions were evaporatedto dryness to afford 4-bromo-5-chloropyridin-2-amine (2.30 g, 43.7%) asa cream solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.) 6.35 (2H, s), 6.82 (1H,s), 8.01 (1H, s). m/z: ES+ [M+H]+ 209 (³⁵Cl ⁸Br and ³⁷Cl ⁷⁹Br isotopes).

Preparation of tert-butyl((1R,3S)-3-((4-bromo-5-chloropyridin-2-yl)carbamoyl)cyclohexyl)carbamate

A solution of(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (1.50g, 6.15 mmol; prepared according to Example 2) dissolved in DCM (20 mL)at 0° C. was treated with 1-chloro-N,N,2-trimethylprop-1-en-1-amine(0.976 mL, 7.38 mmol). The mixture was stirred at r.t. for 1.5 h before4-bromo-5-chloropyridin-2-amine (1.02 g, 4.92 mmol) and pyridine (0.594mL, 7.38 mmol) were added sequentially. The resulting solution wasstirred at r.t. for 16 h. The reaction mixture was diluted with DCM (25mL), and washed sequentially with water (2×25 mL) and saturated aqueoussodium chloride (25 mL). The organic layer was dried over MgSO₄,filtered, and concentrated under reduced pressure. The resulting crudeproduct was purified by ion exchange chromatography, using an SCX-2column. The desired product was eluted from the column using methanol toafford tert-butyl((1R,3S)-3-((4-bromo-5-chloropyridin-2-yl)carbamoyl)cyclohexyl)carbamate(2.34 g, 110%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.) 1.12(1H, dd), 1.22-1.32 (3H, m), 1.38 (9H, s), 1.72 (3H, dd), 1.83-1.94 (2H,m), 2.11 (1H, dt), 8.48 (1H, s), 8.50 (1H, s), 10.77 (1H, s), one protonnot observed. m/z: ES− [M−H]− 430.

Preparation of(1S,3R)-3-amino-N-(4-bromo-5-chloropyridin-2-yl)cyclohexanecarboxamidedihydrochloride

HCl in dioxane (4 M; 5.89 mL, 23.6 mmol) was added to tert-butyl((1R,3S)-3-((4-bromo-5-chloropyridin-2-yl)carbamoyl)cyclohexyl)carbamate(1.20 g, 2.77 mmol) in MeOH (7.01 mL) under air. The resulting solutionwas stirred at ambient temperature for 16 h. The reaction mixture wasevaporated to afford(1S,3R)-3-amino-N-(4-bromo-5-chloropyridin-2-yl)cyclohexanecarboxamidedihydrochloride as a white solid. This was used in the next step withoutfurther purification. m/z: ES+ [M+H]+ 332 (³⁵Cl ⁷⁹Br isotope), 334 (³⁵Cl⁸¹Br and ³⁷Cl ⁷⁹Br isotopes).

Preparation of(1S,3R)-3-acetamido-N-(4-bromo-5-chloropyridin-2-yl)cyclohexanecarboxamide

Acetic anhydride (0.259 mL, 2.74 mmol) was added dropwise to(1S,3R)-3-amino-N-(4-bromo-5-chloropyridin-2-yl)cyclohexanecarboxamide(0.760 g, 2.28 mmol), 4-dimethylaminopyridine (0.014 g, 0.11 mmol) andtriethylamine (0.987 mL, 7.08 mmol) in DCM (8.44 mL) at r.t. undernitrogen. The resulting solution was stirred at r.t. overnight beforebeing quenched with saturated aqueous NH₄Cl (50 mL) and extracted withDCM (2×50 mL). The combined organic layers were dried over MgSO₄,filtered, and concentrated under reduced pressure to afford(1S,3R)-3-acetamido-N-(4-bromo-5-chloropyridin-2-yl)cyclohexanecarboxamide(0.96 g, 95%) as a white solid. The product was used in the next stepwithout further purification. ¹H NMR (400 MHz, DMSO-d₆, 30° C.)1.23-1.41 (4H, m), 1.67-1.85 (4H, m), 2.39 (3H, tt), 2.75-2.92 (1H, m),3.53 (1H, dtd), 7.59-7.83 (1H, m), 8.50 (2H, dd), 10.80 (1H, d). m/z:ES+ [M+H]+ 374 (³⁵Cl ⁷⁹Br isotope), 376 (³⁵Cl ⁸Br and ³⁷Cl ⁷⁹Brisotopes).

Example 8:(1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

(1S,3R)-3-Acetamido-N-(4-bromo-5-chloropyridin-2-yl)cyclohexanecarboxamide(0.100 g, 0.27 mmol; prepared as in Example 7) was added in one portionto a degassed mixture of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine(0.067 g, 0.27 mmol), 2nd Generation X-Phos Precatalyst (0.021 g, 0.03mmol), potassium phosphate (0.170 g, 0.80 mmol), 1,4-dioxane (2.270 mL)and water (0.454 mL) at r.t. The resulting mixture was stirred at r.t.for 16 h and then evaporated to dryness before being purified by ionexchange chromatography using an SCX-2 cartridge. The desired productwas eluted from the column using 1 M NH₃ in MeOH, and pure fractionswere evaporated to dryness to afford crude(1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)pyridin-2-yl)cyclohexanecarboxamideas a yellow gum. The semipure product was purified by preparative HPLC(Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mmlength) using decreasingly polar mixtures of water (containing 1% NH₃)and MeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford(1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.017 g, 16%) as a white gum. ¹H NMR (500 MHz, DMSO-d₆, 30° C.)1.21-1.32 (1H, m), 1.4-1.53 (3H, m), 1.95 (1H, s), 1.96 (3H, s), 2.06(1H, d), 2.39-2.48 (2H, m), 2.7-2.85 (3H, m), 3.74 (1H, dt), 4.34 (2H,t), 4.53-4.68 (2H, m), 7.93 (1H, d), 8.05 (1H, s), 8.48 (1H, d), 8.58(1H, s), 10.62 (1H, s). m/z: ES+ [M+H]+ 418 (¹²C, ³⁵Cl isotope), 419(¹³C, ³⁵Cl isotope secondary peak).

Procedures for preparing the starting material3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazineare described below:

Preparation of 1,2-dihydropyrazol-3-one

To a solution of methyl prop-2-ynoate (150 g, 1785.7 mmol) in MeOH (1500mL) was added hydrazine hydrate (89.2 g, 1784.0 mmol) dropwise at 0° C.The reaction was stirred at r.t. for 30 min. Saturated aqueous sodiumchloride (400 mL) was added, and then methanol was removed under vacuum.The aqueous layer was extracted with EtOAc (3×500 mL), and the combinedorganic layers were dried over Na₂SO₄ and concentrated under reducedpressure to afford 1,2-dihydropyrazol-3-one (99.5 g, 66%) as a whitesolid. m/z: ES+ [M+H]+ 85.

Preparation of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine

To a solution of 1,2-dihydropyrazol-3-one (99.5 g, 1184 mmol) in DMF(4000 mL) was added K₂CO₃ (560.0 g, 4057 mmol), and the mixture washeated at 130° C. for 1 h. Then 1,3-dibromopropane (143.4 mL, 1421 mmol)was added, and the mixture was stirred at 130° C. for 2 h and thenconcentrated. The resulting residue was partitioned between DCM (2000mL) and water (2000 mL). The organic layer was separated and the aqueouslayer was extracted with DCM (3×1000 mL). The combined organic extractswere dried over Na₂SO₄ and concentrated to give6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (83.0 g, 56.8%) as a yellowoil. ¹H NMR (300 MHz, CDCl₃, 30° C.) 2.18-2.11 (2H, m), 4.13-4.05 (2H,m), 4.19-4.16 (2H, m), 5.37-5.37 (1H, m), 7.21-7.20 (1H, m).

Preparation of 3-iodo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine

To a solution of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (83.0 g,669.3 mmol) in CH₃CN (1500 mL) was added N-iodosuccinimide (155.0 g,688.8 mmol). The mixture was stirred at r.t. for 1 h before being slowlypoured into vigorously stirred water (1000 mL). Saturated aqueous sodiumthiosulphate (500 mL) was added, and the resulting mixture was extractedwith ethyl acetate (2×800 mL). The combined organic layers were washedwith water, dried over Na₂SO₄, and concentrated under reduced pressure.The resulting residue was purified by column chromatography on silicagel (petroleum ether:EtOAc=1:1) to give3-iodo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (105.0 g, 62.2%) as ayellow solid. ¹H NMR (300 MHz, DMSO-d₆, 30° C.) 2.19-2.12 (2H, m),4.10-3.98 (2H, m), 4.34-4.31 (2H, m), 7.28 (1H, m). m/z: ES+ [M+H]+ 251.

Preparation of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine

To a solution of 3-iodo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (105g, 420 mmol) in THF (1000 mL) was added2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (126 mL, 630 mmol).The mixture was cooled to 5° C. Then isopropyl magnesium lithiumchloride (410 mL, 420 mmol) was added, and the mixture was stirred at 5°C. for 3 h. The reaction was quenched by addition of MeOH (500 mL) andthen concentrated. The resulting residue was purified by flash silicachromatography, eluting with isocratic 50% ethyl acetate in petroleumether, to afford a pale yellow oil. Crystallisation from heptane (100mL) yielded3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine(38.6 g, 36.7%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.) 1.21(12H, s), 2.15-2.12 (2H, m), 4.06-4.03 (2H, m), 4.31-4.29 (2H, m), 7.32(1H, m). m/z: ES+ [M+H]+ 251.

Example 9:(1R,3S)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamideand(1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(Example 2)

Acetyl chloride (0.280 mL, 3.93 mmol) was added to a solution ofcis-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.639 g, 1.71 mmol; ratio of enantiomers unknown, prepared as inExample 2 from5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amineand cis-3-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid, ratio ofenantiomers unknown) in DCM (14.1 mL) and pyridine (2.77 mL, 34.2 mmol)at 0° C. After 30 min the light yellow reaction was poured into DCM andsaturated aqueous sodium bicarbonate. The layers were separated, and theorganic layer was washed with saturated aqueous sodium chloride anddried over sodium sulfate, filtered, and concentrated under reducedpressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 20% methanol in EtOAc. Productfractions were concentrated under reduced pressure to afford semipureproduct as a white solid. This material was further purified bypreparative HPLC (Waters XBridge Prep C18 column, 5 μm, 30 mm diameter,100 mm length), eluting with 60 to 80% methanol in water (containing0.2% ammonium hydroxide at pH 10) as eluent. Product fractions wereconcentrated to dryness under reduced pressure to affordcis-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide,ratio of enantiomers unknown, as a white solid (403 mg).

This material was transferred to a round-bottom flask using DCM andconcentrated under reduced pressure to a white solid. The solid wastaken up in approximately 10 mL of MeCN and warmed to reflux conditions.The solution was cooled, and a precipitate rapidly started to form.After 10 min the mixture was put in the freezer. After 2 h, the mixturewas warmed to r.t. and stirred vigorously overnight. The white mixturewas then filtered, washed with MeCN first and then hexane. The resultingprecipitate was dried under vacuum at 60° C. for 30 min to afford 159 mgof a crystalline solid (flakes).

Analysis of this solid by analytical SFC conditions (see conditions inExample 2), determined it to be 60.5% e.e. (major component=Example 2).A portion of this material (112 mg) was purified by preparative SFCconditions (Chiralpak IA column, 5 μm, 21.2 mm diameter, 250 mm length,40° C. column temperature, 100 bar outlet pressure, 75 mL/min flowrate), eluting with 40% methanol containing 0.1% dimethylethylamine inCO₂, to afford(1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(70 mg, 67%, Example 2) as a white foam solid and(1R,3S)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(13.2 mg, 11.8%, Example 9) as a white foam solid.

(1R,3S)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

¹H NMR (300 MHz, DMSO-d₆, 27° C.) 0.99-1.17 (1H, m), 1.19-1.37 (3H, m),1.70-1.90 (9H, m), 1.96-2.08 (2H, m), 2.54-2.68 (1H, m), 2.80 (2H, t),3.46-3.68 (1H, m), 4.14 (2H, t), 7.73 (1H, d), 7.76 (1H, s), 8.14 (1H,s), 8.38 (1H, s), 10.57 (1H, s). m/z: ES+ [M+H]+ 416.

Analytical SFC Conditions:

Column: Chiralpak IA column,

Column Dimensions: 5 μm, 4.6 mm diameter, 100 mm length,

Column Temperature: 40° C.

Mobile Phase A: CO₂ (100%)

Mobile Phase B: Methanol containing 0.1% dimethylethylamine

Gradient: Isocratic 40% Mobile Phase B

Outlet Pressure: 100 bar

Flow Rate: 5 mL/min over 5 min

Retention Time: 2.42 min

e.e. >98%

Optical Rotation:

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 25° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: DCM

[α]=−57.1

Example 10:(1S,3R)-3-acetamido-N-(5-chloro-4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide

(1S,3R)-3-Amino-N-(5-chloro-4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.093 g, 0.26 mmol) in DCM (2 mL) was treated with triethylamine (0.079mL, 0.57 mmol) followed by acetic anhydride (0.029 mL, 0.31 mmol). Thereaction mixture was stirred at r.t. for 0.5 h and then washed withwater. The organic layer was purified by flash silica chromatography,elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated todryness to afford(1S,3R)-3-acetamido-N-(5-chloro-4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.075 g, 72%) as a white solid. ¹H NMR (400 MHz, CDCl₃, 30° C.)1.09-1.22 (1H, m), 1.38-1.58 (2H, m), 1.88-2.03 (6H, m), 2.26 (1H, d),2.43-2.56 (1H, m), 2.69 (2H, p), 3.14-3.21 (2H, m), 3.49 (1H, s), 3.87(1H, dtt), 4.21 (2H, t), 5.59 (1H, d), 8.14 (1H, s), 8.22 (1H, s), 8.33(1H, s), 8.43 (1H, s). m/z: ES+ [M+H]+ 402.

Procedures for preparing the starting material(1S,3R)-3-amino-N-(5-chloro-4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of 3-iodo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid (0.75 g, 4.93mmol) dissolved in DMF (4 mL) was treated with N-iodosuccinimide (1.331g, 5.92 mmol) and sodium bicarbonate (0.497 g, 5.92 mmol) at r.t. Themixture was stirred at r.t. for 15 h. The reaction was stirred at 60° C.for a further 16 h and then concentrated under reduced pressure. Theresulting residue was dissolved in EtOAc (50 mL) and washed with water(2×50 mL). The organic layer was concentrated under reduced pressure,and the crude product was purified by flash silica chromatography,elution gradient 0 to 70% EtOAc in heptane. Pure fractions wereevaporated to dryness to afford3-iodo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (0.88 g, 76%) as a beigesolid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.) 2.53-2.6 (2H, m), 2.69-2.79(2H, m), 4.04-4.19 (2H, m), 7.46 (1H, s). m/z: ES+ [M+H]+ 235.

Preparation of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

3-Iodo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (0.800 g, 3.42 mmol) and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.954 g, 5.13mmol) were dissolved in THF (8 mL) at 4° C. and then treated dropwisewith isopropylmagnesium chloride lithium chloride complex in THF (1.3 M;2.63 mL, 3.42 mmol). The mixture was stirred at 4° C. for 2 h and thenconcentrated under reduced pressure. The resulting crude product waspurified by flash silica chromatography, elution gradient 0 to 70% EtOAcin heptane. Pure fractions were evaporated to dryness to afford3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(0.67 g, 84%) as a white solid. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.29(12H, s), 2.60 (2H, p), 2.91-3.02 (2H, m), 4.05-4.19 (2H, m), 7.77 (1H,s). m/z: ES+ [M+H]+ 235.

Preparation of tert-butyl((1R,3S)-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate

1-Chloro-N,N,2-trimethylpropenylamine (1.149 mL, 8.68 mmol) was added toa stirred solution of(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (1.41g, 5.79 mmol; prepared according to Example 2) in DCM (25 mL) cooled inan ice bath under a nitrogen atmosphere. The resulting mixture wasstirred at ambient temperature for 1 h. 5-Chloro-4-iodopyridin-2-amine(1.47 g, 5.79 mmol; prepared according to Example 2) and pyridine (0.702mL, 8.68 mmol) were added, and the resulting mixture was stirred atambient temperature for 16 h. The reaction was quenched by the additionof saturated aqueous NH₄Cl (50 mL). The resulting mixture was extractedwith DCM (3×75 mL), and the combined organic layers were dried overMgSO₄, filtered, and concentrated under reduced pressure. The resultingpale yellow solid was slurried with Et₂O (10 mL) and filtered to yieldtert-butyl((1R,3S)-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate(1.79 g, 3.73 mmol, 64.4%) as a cream-colored solid. ¹H NMR (400 MHz,CDCl₃, 30° C.) 1.04-1.18 (1H, m), 1.24-1.41 (2H, m), 1.44 (9H, s), 1.92(2H, dq), 2.00 (1H, d), 2.28 (1H, d), 2.31-2.41 (1H, m), 3.27-3.62 (2H,m), 4.44 (1H, s), 7.80 (1H, s), 8.19 (1H, s), 8.81 (1H, s). m/z: ES−[M−H]− 478.

Preparation of tert-butyl((1R,3S)-3-((5-chloro-4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate

3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(0.14 g, 0.58 mmol), tert-butyl((1R,3S)-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.18 g, 0.38 mmol), 2nd Generation X-Phos Precatalyst (0.03 g, 0.04mmol) and potassium phosphate, dibasic (0.200 g, 1.15 mmol) weredissolved in 1,4-dioxane (4 mL) and water (0.8 mL) at 21° C. The mixturewas stirred at 21° C. for 18 h. The mixture was then heated at 40° C.for 17 h then at 50° C. for 2 h. The mixture was diluted with EtOAc (30mL) and then washed with water (10 mL). The organic layer wasconcentrated under reduced pressure, and the resulting crude product waspurified by flash silica chromatography, elution gradient 0 to 70% EtOAcin heptane. Pure fractions were evaporated to dryness to affordtert-butyl((1R,3S)-3-((5-chloro-4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.119 g, 67.5%) as a white solid. ¹H NMR (400 MHz, CDCl₃, 30° C.)1.04-1.17 (1H, m), 1.34-1.41 (2H, m), 1.44 (9H, s), 1.89-2.03 (4H, m),2.29 (1H, d), 2.33-2.44 (1H, m), 2.69 (2H, p), 3.14-3.21 (2H, m),3.45-3.59 (1H, m), 4.17-4.24 (2H, m), 4.44 (1H, s), 7.93 (1H, s), 8.15(1H, s), 8.23 (1H, s), 8.33 (1H, s). m/z: ES+ [M+H]+ 460.

Preparation of(1S,3R)-3-amino-N-(5-chloro-4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamidedihydrochloride

To a solution of tert-butyl((1R,3S)-3-((5-chloro-4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.12 g, 0.26 mmol) dissolved in DCM (3 mL) was added HCl (4 M indioxane; 1.294 mL, 5.17 mmol). The mixture was stirred at r.t. for 30minutes before being concentrated under reduced pressure. The resultingcrude product was used directly in the next step. m/z: ES+ [M+H]+ 360.

Example 11:(1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

To a mixture of tert-butyl((1R,3S)-3-((5-chloro-4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.072 g, 0.15 mmol) suspended in DCM (3 mL) at r.t. was added HCl (4 Min dioxane; 0.756 mL, 3.03 mmol). The mixture became a solution whichwas stirred at r.t. for 30 minutes. The reaction was concentrated underreduced pressure to yield crude(1S,3R)-3-amino-N-(5-chloro-4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)pyridin-2-yl)cyclohexanecarboxamidedihydrochloride as a solid. The crude product was dissolved in DCM (2mL), and the resulting solution was treated sequentially withtriethylamine (0.047 mL, 0.33 mmol) and acetic anhydride (0.017 mL, 0.18mmol) at r.t. The reaction mixture was stirred at r.t. for 30 minutesand then concentrated under reduced pressure. The resulting residue waspurified by flash silica chromatography, elution gradient 50 to 100%EtOAc in heptane, then 0 to 10% MeOH in DCM. Pure fractions wereevaporated to dryness to afford(1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.056 g, 88%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.) 1.08(1H, d), 1.29 (4H, q), 1.78 (1H, s), 1.91 (3H, s), 2.61 (2H, s), 3.57(1H, dt), 4.08-4.27 (4H, m), 4.89 (2H, s), 7.74 (1H, d), 7.88 (1H, s),8.01 (1H, s), 8.39 (1H, s), 10.59 (1H, s), 11.90 (1H, s). m/z: ES+[M+H]+ 418.

Procedures for preparing the starting material tert-butyl((1R,3S)-3-((5-chloro-4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamateare described below:

Preparation of 3-iodo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine

6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3-carboxylic acid (0.750 g,4.46 mmol) dissolved in DMF (4 mL) was treated with N-iodosuccinimide(1.204 g, 5.35 mmol) and sodium bicarbonate (0.450 g, 5.35 mmol) at r.t.The mixture was stirred at 70° C. for 4 h and then cooled to r.t. After60 h the mixture was concentrated under reduced pressure, and theresulting residue was dissolved in EtOAc (70 mL) and washed with water(2×70 mL). The organic layer was concentrated under reduced pressure,and the resulting crude product was purified by flash silicachromatography, elution gradient 0 to 70% EtOAc in heptane. Purefractions were evaporated to dryness to afford3-iodo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (0.90 g, 81%). ¹H NMR(400 MHz, DMSO-d₆, 30° C.) 3.98-4.06 (2H, m), 4.07-4.15 (2H, m), 4.65(2H, s), 7.53 (1H, s). m/z: ES+ [M+H]+ 251.

Preparation of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine

3-Iodo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (0.850 g, 3.40 mmol)and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.949 g, 5.10mmol) were dissolved in THF (8 mL) at 4° C. The resulting solution wastreated dropwise with isopropylmagnesium chloride lithium chloridecomplex in THF (1.3 M; 2.61 mL, 3.40 mmol). The reaction mixture wasstirred at 4° C. for 5 h before being concentrated under reducedpressure. The resulting crude product was purified by flash silicachromatography, elution gradient 0 to 70% EtOAc in heptane. Purefractions were evaporated to dryness to afford3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine(0.80 g, 95%) as a colourless gum. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.29(12H, s), 4.08 (2H, dd), 4.17-4.23 (2H, m), 4.96 (2H, s), 7.74 (1H, s).m/z: ES+ [M+H]+ 251.

Preparation of tert-butyl((1R,3S)-3-((5-chloro-4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate

3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine(0.094 g, 0.38 mmol), tert-butyl((1R,3S)-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.120 g, 0.25 mmol; as prepared in Example 10), 2nd Generation X-PhosPrecatalyst (0.020 g, 0.03 mmol) and potassium phosphate dibasic (0.131g, 0.75 mmol) were dissolved in 1,4-dioxane (4 mL) and water (0.800 mL)at 50° C. The mixture was stirred at 50° C. for 1 h and then dilutedwith EtOAc (30 mL). The resulting mixture was washed with water (10 mL),and the organic layer was concentrated under reduced pressure. Theresulting crude product was purified by flash silica chromatography,elution gradient 0 to 70% EtOAc in heptane. Pure fractions wereevaporated to dryness to afford tert-butyl((1R,3S)-3-((5-chloro-4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.081 g, 68%). ¹H NMR (400 MHz, DMSO-d₆, 30° C.) 1.22-1.35 (4H, m),1.38 (9H, s), 1.75 (3H, s), 1.90 (1H, d), 2.54-2.63 (1H, m), 4.12-4.26(4H, m), 4.90 (2H, s), 5.75 (1H, s), 6.76 (1H, d), 7.89 (1H, s), 8.01(1H, s), 8.39 (1H, s), 10.58 (1H, s). m/z: ES+ [M+H]+ 476.

Example 12:(1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide

(1S,3R)-3-Acetamido-N-(5-chloro-4-iodopyridin-2-yl)cyclohexanecarboxamide(130 mg, 0.31 mmol), (6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)boronicacid hydrochloride (145 mg, 0.77 mmol), barium hydroxide (211 mg, 1.23mmol) and PdCl₂(dppf) (22 mg, 0.030 mmol) were suspended in dioxane (2mL) and water (0.4 mL) and sealed into a microwave tube. The reactionwas heated to 75° C. in a microwave reactor and maintained under theseconditions for 2 h before being cooled to r.t. The reaction mixture wasfiltered with a methanol wash, and the filtrate was then concentratedunder reduced pressure. The resulting crude product was purified bypreparative HPLC (Waters XBridge Prep C18 OBD column, 5 m silica, 19 mmdiameter, 100 mm length), using decreasingly polar mixtures of water(containing 1% NH₃) and MeCN as eluents. Fractions containing thedesired compound were evaporated to dryness to afford(1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(21.3 mg, 17.2%) as a solid. ¹H NMR (500 MHz, DMSO-d₆, 30° C.) 1.09 (1H,d), 1.30 (3H, q), 1.78 (5H, s), 1.91 (1H, d), 2.57-2.73 (4H, m), 2.85(2H, t), 3.58 (1H, dd), 4.16 (2H, t), 7.55 (1H, s), 7.75 (1H, d), 8.35(1H, s), 8.42 (1H, s), 10.67 (1H, s). m/z: ES+ [M+H]+ 402.

Procedures for preparing the starting materials(1S,3R)-3-Acetamido-N-(5-chloro-4-iodopyridin-2-yl)cyclohexanecarboxamideand (6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)boronic acidhydrochloride are described below:

Preparation of 5-methoxy-3,4-dihydro-2H-pyrrole

Pyrrolidin-2-one (85 g, 1000 mmol) and Me₂SO₄ (126 g, 1000 mmol) werestirred at r.t. for 30 minutes, and then the mixture was stirred at 60°C. for 6 h. The mixture was slowly poured into a solution oftriethylamine (140 mL) in DCM at 0° C. and stirred under theseconditions for 15 min. Water was added, and the layers were separated.The organic layer was dried over MgSO₄ and concentrated under reducedpressure at r.t. to yield 5-methoxy-3,4-dihydro-2H-pyrrole, which wasused directly in the next step without further purification. ¹H NMR (400MHz, CDCl₃, 30° C.) 2.03-1.95 (2H, m), 2.43-2.39 (2H, m), 3.64-3.60 (2H,m), 3.76 (3H, s).

Preparation of 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

To a solution of 5-methoxy-3,4-dihydro-2H-pyrrole (crude) in DCM (200mL) was added MeOH (800 mL) and aminoacetaldehyde dimethyl acetal (105g, 1000 mmol). The mixture was stirred at 60° C. for 6 h before beingconcentrated under reduced pressure to affordN-(2,2-dimethoxyethyl)-3,4-dihydro-2H-pyrrol-5-amine (82 g, 48%). Thecrude product was dissolved in formic acid (400 mL) and stirred atreflux for 17 h before being concentrated under reduced pressure toafford 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (46 g, 90%). ¹H NMR (400MHz, DMSO-d₆, 30° C.) 2.51-2.44 (2H, m), 2.69-2.65 (2H, m), 3.91-3.88(2H, m), 6.84 (1H, s), 7.02 (1H, s).

Preparation of (6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)boronic acidhydrochloride

To a stirred solution of 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (60 g,560 mmol) in anhydrous THF (700 mL) at −78° C. was added n-BuLi (250 mL,625 mmol), and the mixture was stirred for 1 h at this temperature.Triisopropyl borate (115 g, 610 mmol) was added at −78° C., and then themixture was allowed to warm to r.t. overnight. The reaction was cooledto 0° C., and aqueous HCl (1M; 1000 mL) was added. The reaction wasconcentrated under reduced pressure to remove tetrahydrofuran. The pH ofthe remaining aqueous layer was adjusted to 2 by careful addition ofconcentrated HCl, and the precipitate was collected and dried to afford(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)boronic acid hydrochloride(42 g, 40%). ¹H NMR (400 MHz, DMSO-d₆, 30° C.) 2.64-2.49 (2H, m), 3.08(2H, t), 4.19 (2H, t), 7.92 (1H, s), 8.84 (2H, s), 14.34 (1H, s). m/z:ES+ [M+H]+ 153.

Preparation of3-amino-N-(5-chloro-4-iodopyridin-2-yl)cyclohexanecarboxamide

Tert-butyl(3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate (1 g,2.08 mmol; as prepared in Example 10) was suspended in DCM (15 mL) atambient temperature. HCl (4M) in dioxane (2.61 mL, 10.42 mmol) was addedand the resulting mixture stirred for 16 h. The reaction mixture wasthen loaded onto a 50 g SCX column and eluted sequentially with DCM,MeOH, and 1% NH₃ in MeOH. Basic fractions were concentrated underreduced pressure to afford3-amino-N-(5-chloro-4-iodopyridin-2-yl)cyclohexanecarboxamide as acolourless amorphous solid (782 mg, 99%). m/z: ES+ [M+H]+ 380.

Preparation of(1S,3R)-3-acetamido-N-(5-chloro-4-iodopyridin-2-yl)cyclohexanecarboxamide

Acetic anhydride (0.214 mL, 2.27 mmol) was added to a stirred solutionof (1S,3R)-3-amino-N-(5-chloro-4-iodopyridin-2-yl)cyclohexanecarboxamide(782 mg, 2.06 mmol) and triethylamine (0.632 mL, 4.53 mmol) in DCM (10mL) at ambient temperature. The reaction mixture was stirred for 5 daysbefore being filtered and washed with DCM to provide(1S,3R)-3-acetamido-N-(5-chloro-4-iodopyridin-2-yl)cyclohexanecarboxamide(480 mg, 55%) as a colourless solid. The liquors were concentrated andpurified by flash silica chromatography, elution gradient 20 to 60%EtOAc in heptane. Pure fractions were evaporated to dryness to affordmore(1S,3R)-3-acetamido-N-(5-chloro-4-iodopyridin-2-yl)cyclohexanecarboxamide(193 mg, 22%) as a colourless crystalline solid (combined yield: 77%).¹H NMR (400 MHz, DMSO-d₆, 30° C.) 1.01-1.17 (1H, m), 1.18-1.39 (3H, m),1.68-1.84 (2H, m), 1.78 (3H, s), 1.89 (1H, m), 2.51 (2H, m), 3.48-3.65(1H, m), 7.74 (1H, d), 8.38 (1H, s), 8.71 (1H, s), 10.66 (1H, s). m/z:ES+ [M+H]+ 422.

Example 13:(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

To a solution of tert-butyl((1R,3S)-3-((5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.042 g, 0.090 mmol) dissolved in DCM (2 mL) was added HCl (4 M indioxane; 0.429 mL, 1.72 mmol). The mixture was stirred at r.t. for 2 hbefore being concentrated under reduced pressure to afford a crude solid(33 mg). This solid was dissolved in DCM (2 mL) and triethylamine (0.026mL, 0.19 mmol). Then acetic anhydride (9.6 μL, 0.10 mmol) was added. Themixture was stirred at r.t. for 30 min and then concentrated underreduced pressure. The resulting crude product was purified by flashsilica chromatography, elution gradient 0 to 100% EtOAc in (10% MeOH inDCM). Pure fractions were evaporated to dryness to afford(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.027 g, 74%) as a colourless dry film. ¹H NMR (400 MHz, CDCl₃, 30° C.)1.09-1.24 (1H, m), 1.41-1.56 (3H, m), 1.87-2.04 (6H, m), 2.25 (1H, d),2.51 (4H, s), 2.9-2.98 (2H, m), 3.73 (2H, s), 3.87 (1H, dtd), 4.26 (2H,t), 5.60 (1H, d), 7.84 (1H, s), 8.11 (1H, s), 8.25 (1H, d), 8.30 (1H,s). m/z: ES+ [M+H]+ 431.

Procedures for preparing the starting material tert-butyl((1R,3S)-3-((5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamateare described below:

Preparation of3-bromo-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

HCl (4 M in dioxane; 3.31 mL, 13.24 mmol) was added in one portion totert-butyl 3-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate(0.400 g, 1.32 mmol) in DCM (6 mL) at 20° C. The resulting mixture wasstirred at 20° C. for 60 minutes. A white solid formed. The mixture wasconcentrated under reduced pressure, and the resulting residue wasredissolved in formic acid (12.7 mL, 331 mmol) and treated withformaldehyde (0.64 mL, 8.6 mmol). This new mixture was heated at 100° C.for 8 h before being concentrated under reduced pressure. The resultingresidue was dissolved in EtOAc (25 mL) and then washed with saturatedaqueous sodium hydrogencarbonate (2×25 mL); the combined aqueous layerswere then extracted with EtOAc (2×25 mL). The combined organic layerswere concentrated under reduced pressure, and the resulting cruderesidue was purified by flash silica chromatography, elution gradient 0to 100% EtOAc in heptane. Pure fractions were evaporated to dryness toafford 3-bromo-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.185g, 64.7%) as a colourless oil. ¹H NMR (400 MHz, CDCl₃, 30° C.) 2.45 (3H,s), 2.75-2.85 (2H, m), 3.48 (2H, s), 4.05-4.15 (2H, m), 7.35 (1H, s).m/z: ES+ [M+H]+ 218 (⁸¹Br isotope).

Preparation of5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

3-Bromo-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.185 g,0.860 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(0.435 g, 1.71 mmol), potassium acetate (0.294 g, 3.00 mmol) andPd(P(Cy)₃)₂Cl₂ (0.063 g, 0.090 mmol) were suspended in DMA (3 mL). Thereaction was heated to 80° C. for 5 h then 90° C. for 16 h. The reactionmixture was cooled to r.t. and then diluted with water (20 mL) andextracted with EtOAc (20 mL). The combined organics were concentratedunder reduced pressure. The resulting crude product was purified byflash silica chromatography, elution gradient 0 to 100% DCM in heptanefollowed by 0 to 10% MeOH in DCM. Pure fractions were evaporated todryness to afford5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine(0.20 g, 89%) as a colourless oil. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.29(12H, s), 2.52 (3H, s), 2.88-2.92 (2H, m), 3.80 (2H, s), 4.22 (2H, t),7.72 (1H, s). m/z: ES+ [M+H]+ 264.

Preparation of tert-butyl((1R,3S)-3-((5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate

Tert-butyl((1R,3S)-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.200 g, 0.42 mmol; as prepared in Example 10),5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine(0.197 g, 0.750 mmol), 2nd Generation X-Phos Precatalyst (0.033 g, 0.040mmol) and potassium phosphate dibasic (0.218 g, 1.25 mmol) weredissolved in 1,4-dioxane (4 mL) and water (0.800 mL) at 45° C. Themixture was stirred at 45° C. for 18 h. More 2nd Generation X-PhosPrecatalyst (0.033 g, 0.04 mmol) was added, and the temperature wasraised to 60° C. for 1 h. The reaction mixture was cooled and passedthrough an SCX-2 column. The desired product was eluted from the columnusing 1 M NH₃ in MeOH, and pure fractions were concentrated underreduced pressure. The resulting crude product was purified by flashsilica chromatography, elution gradient 0 to 100% EtOAc in heptane, then0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness toafford tert-butyl((1R,3S)-3-((5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.054 g, 27%). ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.04-1.19 (1H, m), 1.44(12H, s), 1.87-2.02 (3H, m), 2.29 (1H, d), 2.33-2.46 (1H, m), 2.53 (3H,s), 2.95-3 (2H, m), 3.50 (1H, s), 3.76 (2H, s), 4.28 (2H, t), 4.52 (1H,s), 7.85 (1H, s), 8.12 (2H, s), 8.26 (1H, s). m/z: ES+ [M+H]+ 489.

Example 14:(1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide

To a stirred solution of(1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(111 mg, 0.290 mmol), triethylamine (0.084 mL, 0.60 mmol) andN,N-dimethylpyridin-4-amine (1.748 mg, 0.01 mmol) in DCM (10 mL) wasadded acetic anhydride (0.032 mL, 0.34 mmol). The reaction mixture wasstirred at r.t. for 4 h and then purified by ion exchange chromatographyusing an SCX-2 column. The desired product was eluted from the columnusing 1 M NH₃ in MeOH, and product-containing fractions wereconcentrated under reduced pressure. The resulting crude product waspurified by flash silica chromatography, elution gradient 0 to 100%EtOAc in heptane. Pure fractions were evaporated to dryness to afford(1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(86 mg, 70%) as a white solid (Form A). ¹H NMR (400 MHz, DMSO-d₆, 30°C.) 1.09 (1H, d), 1.28 (9H, s), 1.78 (6H, s), 1.90 (1H, d), 2.62 (1H,s), 2.89 (2H, s), 3.57 (1H, dt), 3.95 (2H, s), 7.73 (1H, d), 7.99 (1H,s), 8.25 (1H, s), 8.33-8.36 (1H, m), 10.53 (1H, s). m/z: ES+ [M+H]+ 430.

Optical Rotation

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 20° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: DMSO

[α]=+66.4

Method 1: The title material (10 mg) was dissolved in 1 mL ofacetonitrile and the clear solution was slowly evaporated at r.t. over 3days. The resulting solid was found to be the Example 14 in crystallineForm A.

Method 2: The title material (10 mg) was added to 0.1 mL acetonitrileand the resulting suspension was stirred at ambient temperature for 18 hand then air dried over 3 days. The resulting solid was found to beExample 14 in crystalline Form A.

Crystals of Form A were analyzed by XRPD and results are tabulated belowand are shown in FIG. 1. The XRPD of the solid confirms that the solidcontains exclusively Form A which has an X-ray powder diffractionpattern with specific peaks at about 2-theta=5.9, 7.0, 9.4, 10.5, 11.5,11.7, 17.6, 18.0, 20.2 and 21.0°.

Example 14 Form A Main Peaks

Peak 2θ Intensity % 1 5.9 83.1 (vs) 2 7.0 100.0 (vs)  3 9.4 69.8 (vs) 410.5 71.7 (vs) 5 11.5 59.6 (vs) 6 11.7 59.4 (vs) 7 17.6 53.7 (vs) 8 18.061.0 (vs) 9 20.2 77.3 (vs) 10 21.0 88.7 (vs)

Crystals (Form A) obtained according to the Example 14 were analyzed bythermal techniques. DSC analysis indicated that Form A melts with anonset point at 1910 and a peak at 1930. TGA indicated that Form Aexhibits a mass loss of about 1.6% upon heating from 22 to 200° C. Arepresentative DSC/TGA thermogram is shown in FIG. 2.

An alternative procedure for making Example 14 is described in Example85.

Procedures for preparing the starting material(1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of ethyl 2,2-dimethyl-3-(1H-pyrazol-1-yl)propanoate

1H-Pyrazole (20 g, 293.78 mmol), ethyl 3-bromo-2,2-dimethylpropanoate(61.4 g, 293.78 mmol) and cesium carbonate (144 g, 440.68 mmol) in DMA(200 mL) were stirred at 80° C. for 16 h. The mixture was then pouredinto water (400 mL) and extracted with ethyl acetate (150 mL). Theorganic layer was concentrated under reduced pressure to give acolourless oil. This oil was purified by flash silica chromatography,elution gradient 10 to 40% ethyl acetate in heptane). Product fractionswere concentrated under reduced pressure to afford ethyl2,2-dimethyl-3-(1H-pyrazol-1-yl)propanoate (46.0 g, 80.0%), as acolourless oil. ¹H NMR (400 MHz, CDCl₃, 30° C.) 0.97 (6H, s), 1.02 (3H,t), 3.93 (2H, q), 4.10 (2H, s), 6.00 (1H, t), 7.16 (1H, d), 7.26 (1H,d). m/z: (ES+) [M+H]+=197.

Preparation of 2,2-dimethyl-3-(1H-pyrazol-1-yl)propanoic acid

Aqueous sodium hydroxide (5 M; 94 mL, 46 mmol) was added portionwise toa stirred solution of ethyl 2,2-dimethyl-3-(1H-pyrazol-1-yl)propanoate(46 g, 234 mmol) dissolved in methanol (250 mL) at r.t. The mixture wasallowed to exotherm to 37° C. during addition. The resulting solutionwas stirred under these conditions for 30 minutes and then cooled tor.t. before being concentrated under reduced pressure to ⅓ volume. Thisnew solution was acidified to ˜pH 3 with concentrated HCl. A colourlessoil separated from the mixture. The flask was swirled in an ice bath anda colourless solid crystallised. The mixture was allowed to standovernight at r.t., and the solid was isolated by filtration and driedunder reduced pressure to afford2,2-dimethyl-3-(1H-pyrazol-1-yl)propanoic acid (30.0 g, 76%) as acolourless crystalline solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.) 1.05(6H, s), 4.23 (2H, s), 6.21 (1H, t), 7.35-7.44 (1H, m), 7.54-7.67 (1H,m), 12.41 (1H, br s). m/z: (ES+) [M+H]+=169.

Preparation of 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-one

n-BuLi in hexane (9.03 mL, 24.38 mmol) was added dropwise to2,2-dimethyl-3-(1H-pyrazol-1-yl)propanoic acid (2 g, 11.89 mmol) in2-methyl tetrahydrofuran (40 mL) at −78° C. over a period of 20 minutesunder nitrogen. The resulting suspension was stirred at −78° C. for 15minutes, and then the reaction was stirred at approximately −45° C. for1 h then allowed to warm to 15° C. before the reaction was quenchedslowly onto ice cold saturated ammonium chloride (100 ml). The reactionmixture was diluted with EtOAc (100 mL) and the ammonium chloride layerwas separated and extracted one more time with EtOAc (50 ml). Thecombined organics layers were washed with saturated aqueous sodiumchloride (50 mL). The organic layer was dried over MgSO₄, filtered andevaporated to afford5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-one (0.970 g, 54.3%)as a pale yellow oil which crystallised on standing. ¹H NMR (400 MHz,DMSO-d₆, 30° C.) 1.29 (6H, s), 4.36 (2H, s), 6.77 (1H, d), 7.89 (1H, d).m/z: ES+ [M+H]+ 151.

Preparation of 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

Hydrazine hydrate (4.13 mL, 85.23 mmol) was added to a stirred solutionof 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-one (2.56 g, 17.1mmol) dissolved in 2,2′-oxydiethanol (48.5 mL, 511 mmol). The resultingsolution was stirred at 180° C. for 1 h. Potassium hydroxide (3.35 mL,59.7 mmol) was carefully added to the mixture and the resultingsuspension was stirred at 150° C. for 2 h. After cooling to r.t., thereaction mixture was diluted with water (50 mL), and the pH was adjustedto 4.5 with dilute aqueous HCl (2N). Following extraction with Et₂O(5×50 mL), the combined organic layers were washed with water (2×20 mL)and then saturated aqueous sodium chloride (20 mL). The organic layerswere dried over MgSO₄, filtered and concentrated under reduced pressureto give 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (0.922 g,39.7%) as a clear yellow oil. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.21 (6H,s), 2.61 (2H, s), 3.80 (2H, s), 5.82-5.93 (1H, m), 7.41 (1H, d).

Preparation of3-bromo-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

N-Bromosuccinimide (1166 mg, 6.55 mmol) was added to a stirred solutionof 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (892 mg, 6.55mmol) dissolved in DCM (10 mL) at 23° C. The resulting mixture wasstirred at 23° C. for 16 h before being diluted with DCM (20 mL) andwashed sequentially with water (2×20 mL) and saturated aqueous sodiumchloride (20 mL). The organic layer was dried over MgSO₄, filtered, andconcentrated under reduced pressure to afford3-bromo-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (1394 mg,99%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.23 (6H, s), 2.58(2H, s), 3.83 (2H, s), 7.35 (1H, s).

Preparation of5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

Pd(P(Cy)₃)₂Cl₂ (0.247 g, 0.33 mmol) was added to4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.70 g,6.69 mmol), 3-bromo-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(0.720 g, 3.35 mmol) and potassium acetate (1.150 g, 11.72 mmol) in DMA(7 mL). The resulting suspension was degassed and stirred at 85° C. for5 h. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium DCM adduct(0.273 g, 0.33 mmol) was then added to the reaction mixture, andstirring was continued under these conditions for 18 h before thereaction mixture was cooled to r.t. The reaction mixture was dilutedwith EtOAc (20 mL) and washed sequentially with water (2×15 mL), andsaturated aqueous sodium chloride (15 mL). The organic layer was driedover MgSO₄, filtered, and concentrated under reduced pressure. Theresulting crude product was purified by flash silica chromatography,elution gradient 0 to 50% EtOAc in heptane. Pure fractions wereevaporated to dryness to afford5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(0.458 g, 52.2%) as a cream solid. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.24(6H, s), 1.27 (12H, s), 2.79 (2H, s), 3.87 (2H, s), 7.76 (1H, s).

Preparation of tert-butyl((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate

5,5-Dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(433 mg, 0.83 mmol), tert-butyl((1R,3S)-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate(360 mg, 0.75 mmol; as prepared in Example 10), 2nd Generation X-PhosPrecatalyst (59.0 mg, 0.08 mmol) and potassium phosphate dibasic (392mg, 2.25 mmol) were dissolved in 1,4-dioxane (4 mL) and water (0.8 mL)and stirred at 50° C. for 5 h. The reaction mixture was cooled to r.t.and then purified by ion exchange chromatography using an SCX-2 column.The desired product was eluted from the column using 1 M NH₃ in MeOH,and pure fractions were concentrated under reduced pressure. Theresulting crude product was purified by flash silica chromatography,elution gradient 0 to 100% EtOAc in heptane. Pure fractions wereevaporated to dryness to afford tert-butyl((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(188 mg, 51.3%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, 23° C.) 1.25(12H, d), 1.37 (7H, s), 1.74 (3H, s), 1.87 (1H, d), 2.52-2.62 (1H, m),2.88 (2H, s), 3.18-3.29 (1H, m), 3.93 (2H, s), 6.80 (1H, d), 7.99 (1H,s), 8.24 (1H, s), 8.32-8.35 (1H, m), 10.56 (1H, s). m/z: ES+ [M+H]+ 488.

Preparation of(1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Tert-butyl((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(186 mg, 0.380 mmol) was dissolved in HCl in dioxane (4 M; 0.810 mL,3.24 mmol) and MeOH (5 mL) and stirred at r.t. for 18 h. The reactionmixture was purified by ion exchange chromatography using an SCX-2column. The desired product was eluted from the column using 1 M NH₃ inMeOH, and pure fractions were evaporated to dryness to afford(1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(114 mg, 77%) as a white solid which was used directly in the next step.m/z: ES+ [M+H]+ 388.

Example 15:(1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Acetic anhydride (0.021 mL, 0.22 mmol) was added dropwise to(1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.066 g, 0.18 mmol), 4-dimethylaminopyridine (1.141 mg, 9.34 μmol) andtriethylamine (0.081 mL, 0.58 mmol) in DCM (1 mL) at r.t. undernitrogen. The resulting solution was stirred at r.t. for 2 h beforebeing quenched with saturated aqueous NH₄Cl (10 mL). The resultingmixture was extracted with DCM (2×10 mL). The combined organic layerswere dried over MgSO₄, filtered, and concentrated under reducedpressure. The resulting white solid was purified by flash silicachromatography, elution gradient 0 to 100% EtOAc in heptane. Fractionswere evaporated to dryness to afford semipure product which was furtherpurified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 μmsilica, 30 mm diameter, 100 mm length) using decreasingly polar mixturesof water (containing 1% NH₃) and MeCN as eluents. Fractions containingthe desired compound were evaporated to dryness to afford(1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(9.80 mg, 12.6%). ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.13 (1H, dd),1.31-1.52 (4H, m), 1.87-1.95 (2H, m), 1.96 (4H, s), 2.20 (3H, dd),2.39-2.5 (1H, m), 3.39-3.45 (2H, m), 4.16 (2H, t), 4.81 (1H, s), 5.49(1H, d), 7.79 (1H, s), 8.14 (1H, s), 8.19 (1H, s), 8.30 (1H, s). m/z:ES+ [M+H]+ 417.

Procedures for preparing the starting material(1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of 3-iodo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine

N-Iodosuccinimide (0.581 g, 2.58 mmol) was added to4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (0.265 g, 2.15 mmol) inacetonitrile (5 mL) at r.t. under nitrogen. The resulting solution wasstirred at r.t. for 1 h before water (20 mL) was added. Stirring wascontinued for 1.5 h, and then the reaction mixture was extracted withMTBE (3×20 mL). The combined organic layers were washed sequentiallywith 2 M aqueous NaOH (20 mL), Na₂S₂O₃ solution (20 mL, 10% w/v), andsaturated aqueous sodium chloride (20 mL) before being dried over MgSO₄,filtered, and concentrated under reduced pressure. The resulting crudeproduct was purified by flash silica chromatography, elution gradient 0to 100% EtOAc in heptane. Pure fractions were evaporated to dryness toafford 3-iodo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (0.155 g,28.9%) as a white crystalline solid. ¹H NMR (400 MHz, CDCl₃, 30° C.)2.16 (2H, q), 3.32-3.44 (2H, m), 3.98 (1H, s), 4.12 (2H, t), 7.24 (1H,s). m/z: ES+ [M+H]+ 250.

Preparation of tert-butyl((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate

3-Iodo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (0.150 g, 0.600 mmol)and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.184 mL, 0.9mmol) were dissolved in THF (4 mL) at 4° C. Then isopropylmagnesiumchloride lithium chloride complex in THF (1.3 M; 2.78 mL, 3.61 mmol) wasadded dropwise. The resulting mixture was stirred at 4° C. for 16 h,then further isopropylmagnesium chloride lithium chloride complex in THF(1.3 M; 2.78 mL, 3.61 mmol) and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.184 mL, 0.90mmol) were added. The reaction was stirred under these conditions for 1h and then concentrated under reduced pressure. The resulting residuewas redissolved in EtOAc (20 mL) and washed sequentially with saturatedaqueous NH₄Cl (25 mL), water (20 mL), and saturated saturated sodiumchloride (20 mL). The combined aqueous layers were washed with DCM (2×20mL). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford crude3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinewhich was added to tert-butyl((1R,3S)-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.160 g, 0.33 mmol; as prepared in Example 10), 2nd Generation X-PhosPrecatalyst (0.026 g, 0.03 mmol) and potassium phosphate tribasic (0.175g, 1.00 mmol) dissolved in 1,4-dioxane (4 mL) and water (0.8 mL) at 50°C. The resulting mixture was stirred at 50° C. for 2 h and then at 80°C. for 16 h. The reaction mixture was concentrated under reducedpressure and the resulting residue was redissolved in DCM (20 mL) andwashed with water (20 mL). The organic layer was dried over MgSO₄,filtered and concentrated under reduced pressure to afford crude productwhich was purified by flash silica chromatography, elution gradient 0 to30% EtOAc in heptane. Pure fractions were evaporated to dryness toafford tert-butyl((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.082 g, 52%) as a yellow gum. 1H NMR (400 MHz, CDCl₃, 30° C.) 1.44(12H, s), 1.82-2.46 (8H, m), 3.27-3.36 (3H, m), 4.12 (3H, t), 5.33 (1H,d), 7.80 (1H, s), 8.13 (1H, s), 8.19 (1H, s), 8.20 (1H, s). m/z: ES+[M+H]+ 475.

Preparation of(1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)cyclohexanecarboxamidetrihydrochloride

Tert-butyl((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.086 g, 0.18 mmol) and HCl in dioxane (4 M; 0.362 mL, 1.45 mmol) weredissolved in methanol (2 mL) at r.t. under air. The resulting solutionwas stirred at r.t. for 3 h before being concentrated under reducedpressure. The resulting material (66 mg) was used directly in the nextstep without further purification. m/z: ES+ [M+H]+ 375.

Example 16:(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide

To a stirred solution of(1S,3R)-3-amino-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(65 mg, 0.18 mmol), triethylamine (0.054 mL, 0.39 mmol) andN,N-dimethylpyridin-4-amine (1.123 mg, 9.19 μmol) in DCM (5 mL) wasadded acetic anhydride (0.021 mL, 0.22 mmol). The reaction mixture wasstirred at r.t. for 1 h. The crude product was purified by ion exchangechromatography using an SCX-2 column. The desired product was elutedfrom the column using 1 M NH₃ in MeOH, and fractions were evaporated toafford(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(60.0 mg, 82.0%) as a colourless oil which was crystallised from anether/heptane mix to afford a white solid. ¹H NMR (400 MHz, DMSO-d₆, 30°C.) 1.10 (1H, t), 1.29 (9H, s), 1.79 (6H, s), 1.85-1.94 (1H, m),2.57-2.66 (1H, m), 2.93 (2H, s), 3.58 (1H, dt), 3.90 (2H, s), 7.21 (1H,dd), 7.74 (1H, d), 7.96 (1H, s), 8.18-8.24 (2H, m), 10.32 (1H, s). m/z:ES+ [M+H]+ 396.

Procedures for preparing the starting material(1S,3R)-3-amino-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of tert-butyl((1R,3S)-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate

Tert-butyl((1R,3S)-3-((4-bromopyridin-2-yl)carbamoyl)cyclohexyl)carbamate (1.50 g,3.77 mmol; as prepared in Example 3), potassium acetate (1.11 g, 11.3mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.44g, 5.65 mmol), and PdCl₂(dppf) (0.276 g, 0.380 mmol) were charged to aflask. 1,4-Dioxane (30 mL) was added, and the mixture heated at 90° C.under nitrogen for 3 h. The mixture was allowed to cool, and the solidswere removed by filtration. Ethyl acetate (100 mL) and water (50 mL)were added, and the layers were separated. The aqueous layer wasextracted with EtOAc (2×50 mL), and the combined organic layers weredried over Na₂SO₄ and concentrated under reduced pressure to afford thecrude product, tert-butyl((1R,3S)-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(2.76 g), as a dark brown oil. This oil was used directly in the nextstep without further purification. m/z: ES+ [M+H]+ 446.

Preparation of tert-butyl((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate

Dichloro[1,1′-bis(di-t-butylphosphino)ferrocene]palladium(II) (45.5 mg,0.07 mmol) was added to a degassed solution of tert-butyl((1R,3S)-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(518 mg, 0.70 mmol),3-bromo-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (150 mg, 0.70mmol; as prepared in Example 14) and potassium phosphate tribasic (444mg, 2.09 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL). The resultingmixture was stirred at 90° C. for 18 h and then purified by ion exchangechromatography using an SCX-2 column. The desired product was elutedfrom the column using 1 M NH₃ in MeOH, and pure fractions wereconcentrated under reduced pressure to afford crude product as a brownoil. This oil was purified by flash silica chromatography, elutiongradient 0 to 100% EtOAc in heptane. Pure fractions were evaporated todryness to afford tert-butyl((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(100 mg, 31.6%) as a white solid. m/z: ES+ [M+H]+ 454.

Preparation of(1S,3R)-3-amino-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Tert-butyl((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(93 mg, 0.21 mmol) was dissolved in HCl in dioxane (4 M; 0.436 mL, 1.74mmol) and MeOH (5 mL), and the reaction mixture was stirred at r.t. for18 h. The reaction mixture was then purified by ion exchangechromatography using an SCX-2 column. The desired product was elutedfrom the column using 1 M NH₃ in MeOH, and fractions were concentratedunder reduced pressure. The resulting crude product was further purifiedby flash silica chromatography, elution gradient 0 to 10% (7N ammonia inmethanol) in DCM. Pure fractions were evaporated to dryness to afford(1S,3R)-3-amino-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(68.0 mg, 94%) as a white solid. m/z: ES+ [M+H]+ 354.

Example 17:(1S,3R)—N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide

HATU (108 mg, 0.28 mmol) was added to a solution of1-hydroxycyclopropanecarboxylic acid (35 mg, 0.34 mmol),(1S,3R)-3-amino-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(100 mg, 0.28 mmol; prepared according to Example 16), and triethylamine(0.12 mL, 0.85 mmol) in DMF (1 mL). The reaction mixture was heated at50° C. for 4 h and then cooled to r.t. The reaction mixture was purifieddirectly by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μsilica, 19 mm diameter, 100 mm length), using decreasingly polarmixtures of water (containing 1% NH₃) and MeCN as eluents. Fractionscontaining the desired compound were concentrated under reduced pressureto afford(1S,3R)—N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide(92 mg, 74%) as a solid. ¹H NMR (500 MHz, DMSO-d₆, 30° C.) 0.74 (2H, m),0.85-1.01 (2H, m), 1.15-1.27 (9H, m), 1.44 (1H, q), 1.61-1.77 (3H, m),1.79-1.87 (1H, br. d), 2.52-2.59 (1H, m), 2.86 (2H, s), 3.54-3.63 (1H,m), 3.83 (2H, s), 6.10 (1H, s), 7.12-7.16 (1H, m), 7.57 (1H, d), 7.90(1H, s), 8.13-8.16 (2H, m), 10.27 (1H, s). m/z: ES+ [M+H]+ 438.

Example 18:N-((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide

HATU (77 mg, 0.20 mmol) was added to a solution of oxetane-3-carboxylicacid (25 mg, 0.24 mmol),(1S,3R)-3-amino-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(72 mg, 0.20 mmol; prepared according to Example 16), and triethylamine(0.085 mL, 0.61 mmol) in DMF (1 mL). The mixture was stirred at r.t. for4 hh and then purified directly by preparative HPLC (Waters XBridge PrepC18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), usingdecreasingly polar mixtures of water (containing 1% NH₃) and MeCN aseluents. Fractions containing the desired compound were concentratedunder reduced pressure to affordN-((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide(17 mg, 19%) as a solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.) 1.06-1.17(1H, m), 1.26-1.39 (9H, m), 1.77-1.86 (3H, m), 1.91-1.94 (1H, br d),2.57-2.7 (1H, m), 2.93 (2H, s), 3.54-3.76 (2H, m), 3.90 (2H, s),4.4-4.71 (4H, m), 7.21 (1H, dd), 7.82 (1H, d), 7.96 (1H, s), 8.21-8.24(2H, m), 10.33 (1H, s). m/z: ES+ [M+H]+ 438.

Example 19:N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide

HATU (118 mg, 0.31 mmol) was added to a solution of oxetane-3-carboxylicacid (32 mg, 0.31 mmol),(1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(100 mg, 0.26 mmol; prepared according to Example 14), and triethylamine(0.11 mL, 0.77 mmol) in DMA (2 mL). The mixture was stirred at r.t. for16 h before being quenched with water (20 mL). The mixture was thenextracted with DCM (50 mL), and the organic layer was washed withsaturated aqueous sodium chloride (50 mL) before being passed through aphase separation cartridge. The combined organics were dried over MgSO₄,filtered, and concentrated under reduced pressure. The resulting residuewas purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5asilica, 30 mm diameter, 100 mm length), using decreasingly polarmixtures of water (containing 1% NH₃) and MeCN as eluents. Fractionscontaining the desired compound were concentrated under reduced pressureto affordN-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide(39 mg, 32%) as a solid. ¹H NMR (500 MHz, DMSO-d₆, 30° C.) 1.06-1.14(1H, m), 1.62-1.75 (9H, m), 1.72-1.81 (3H, m), 1.92 (1H, br. d),2.59-2.7 (1H, m), 2.90 (2H, s), 3.56-3.73 (2H, m), 3.95 (2H, s),4.53-4.66 (4H, m), 7.80 (1H, d), 8.00 (1H, s), 8.25 (1H, s), 8.35 (1H,s), 10.56 (1H, s). m/z: ES+ [M+H]+ 472.

Example 20:(1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-((S)-2-hydroxypropanamido)cyclohexanecarboxamide

HATU (78 mg, 0.21 mmol) was added to a solution of(S)-2-hydroxypropanoic acid (19 mg, 0.21 mmol),(1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(80 mg, 0.21 mmol; prepared according to Example 14), and triethylamine(0.086 mL, 0.62 mmol) in DMF (1 mL). The mixture was stirred at r.t. for1 h and then purified directly by preparative HPLC (Waters XBridge PrepC18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), usingdecreasingly polar mixtures of water (containing 1% NH₃) and MeCN aseluents. Fractions containing the desired compound were concentratedunder reduced pressure to afford(1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-((S)-2-hydroxypropanamido)cyclohexanecarboxamide(56 mg, 59%) as a solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 1.14-1.21(3H, m), 1.23-1.54 (10H, m), 1.66-1.91 (4H, m), 2.56-2.70 (1H, m), 2.90(2H, s), 3.53-3.72 (1H, m), 3.87-3.97 (3H, m), 5.37 (1H, d), 7.49 (1H,d), 8.00 (1H, s), 8.25 (1H, s), 8.35 (1H, s), 10.55 (1H, s). m/z: ES+[M+H]+ 460.

Example 21:(1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide

HATU (78 mg, 0.21 mmol) was added to a solution of1-hydroxycyclopropanecarboxylic acid (25 mg, 0.25 mmol),(1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(80 mg, 0.21 mmol; prepared according to Example 14), and triethylamine(0.086 mL, 0.62 mmol) in DMF (1 mL). The mixture was heated at 50° C.for 3 h then cooled to r.t. The reaction mixture was purified directlyby preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30mm diameter, 100 mm length), using decreasingly polar mixtures of water(containing 1% NH₃) and MeCN as eluents. Fractions containing thedesired compound were concentrated under reduced pressure to afford(1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide(25 mg, 26%) as a solid. ¹H NMR (500 MHz, DMSO-d₆, 30° C.) 0.72-0.85(2H, m), 0.94-1.08 (2H, m), 1.23-1.49 (9H, m), 1.47-1.58 (1H, m),1.67-1.84 (3H, m), 1.87 (1H, br. d), 2.57-2.66 (1H, m), 2.90 (2H, s),3.60-3.71 (1H, m), 3.95 (2H, s), 6.16 (1H, s), 7.62 (1H, d), 8.01 (1H,s), 8.26 (1H, s), 8.35 (1H, s), 10.55 (1H, s). m/z: ES+ [M+H]+ 472.

Example 22:(1S,3R)-3-acetamido-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide

(1S,3R)-3-Acetamido-N-(5-chloro-4-iodopyridin-2-yl)cyclohexanecarboxamide(800 mg, 1.90 mmol; prepared according to Example 12),6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (825 mg, 5.69 mmol),palladium acetate (171 mg, 0.76 mmol) and potassium acetate (372 mg,3.79 mmol) were suspended in DMA (15 mL) and sealed into a microwavetube. The tube was degassed and purged with nitrogen (3×). The reactionwas then subjected to microwave conditions (150° C., 16 h) and cooled tor.t. The reaction mixture was purified by preparative HPLC (WatersXBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length),using decreasingly polar mixtures of water (containing 1% NH₃) and MeCNas eluents. Fractions containing the desired compound were concentratedunder reduced pressure. The resulting light brown solid wasrecrystallised using EtOAc/heptane and dried under vacuum to give(1S,3R)-3-acetamido-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(180 mg, 22%) as a white solid. The filtrate was concentrated underreduced pressure to provide a second batch of(1S,3R)-3-acetamido-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(118 mg, 14%). ¹H NMR (500 MHz, DMSO-d₆, 30° C.) 1.03-1.16 (1H, m),1.19-1.41 (9H, m), 1.72-1.81 (6H, m), 1.91 (1H, br. d), 2.57-2.68 (1H,m), 2.71 (2H, s), 3.50-3.62 (1H, m), 3.91 (2H, s), 7.51 (1H, s), 7.75(1H, d), 8.28 (1H, s), 8.42 (1H, s), 10.66 (1H, s). m/z: ES+ [M+H]+ 430.

Preparation of 4,4-dimethylpyrrolidine-2-thione

Lawesson's Reagent (9.83 g, 24.30 mmol) was added to a stirred solutionof 4,4-dimethylpyrrolidin-2-one (5.0 g, 44.19 mmol) in toluene (100 mL).The resulting mixture was heated under reflux conditions under nitrogenfor 4.5 h. The mixture was then cooled to r.t. and maintained underthese conditions for 18 h before being concentrated under reducedpressure to provide a yellow solid. The solid was dissolved in DCM,silica was added, and the mixture was filtered. The filtrate wasconcentrated under reduced pressure to provide a yellow oil. This oilwas purified by flash silica chromatography, eluting with DCM, to afford4,4-dimethylpyrrolidine-2-thione (2.8 g, 48%) as a colourlesscrystalline solid. Impure fractions were concentrated under reducedpressure to provide a second batch of 4,4-dimethylpyrrolidine-2-thioneas cream/pale yellow crystals (3.1 g, 55%). Despite a slightly lowerpurity, this second batch of material was also suitable for use insubsequent steps. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.19 (6H, s), 2.70(2H, s), 3.36 (2H, s), 7.75 (1H, br. s).

Preparation of 3,3-dimethyl-5-(methylthio)-3,4-dihydro-2H-pyrrolehydroiodide

Iodomethane in MTBE (2 M; 42.7 mL, 85.4 mmol) was added to a stirredsolution of 4,4-dimethylpyrrolidine-2-thione (2.76 g, 21.3 mmol) iniPrOH (45 mL) at r.t. A white precipitate formed over time. The reactionwas stirred at r.t. for 18 h and then filtered. The collected solid waswashed with Et₂O and then dried to provide3,3-dimethyl-5-(methylthio)-3,4-dihydro-2H-pyrrole as the hydroiodidesalt (4.3 g, 75%). This material was carried into the next stage withoutfurther purification. ¹H NMR (500 MHz, DMSO-d₆, 27° C.) 1.17 (6H, s),2.74 (3H, s), 3.10 (2H, s), 3.72 (2H, s), 12.3 (1H, br. s).

Preparation ofN-(2,2-dimethoxyethyl)-3,3-dimethyl-3,4-dihydro-2H-pyrrol-5-aminehydroiodide

2,2-Dimethoxyethanamine (1.82 mL, 16.7 mmol) was added to a stirredsuspension of 3,3-dimethyl-5-(methylthio)-3,4-dihydro-2H-pyrrolehydroiodide (4.32 g, 15.9 mmol) in ethanol (40 mL) at r.t. Thehydroiodide salt dissolved upon addition of the amine. The resultingmixture was heated under reflux conditions (using a bleach scrubber) for4.5 h and then removed from heat. After another 18 h the reactionmixture was concentrated under reduced pressure to provide crudeN-(2,2-dimethoxyethyl)-3,3-dimethyl-3,4-dihydro-2H-pyrrol-5-aminehydroiodide (5.35 g, 102%) as a colourless crystalline solid. ¹H NMR(400 MHz, DMSO-d₆, 30° C.) 1.12 (6H, s), 2.58-2.7 (2H, m), 3.34 (8H, s),3.37 (2H, d), 4.51 (1H, m), 9.35 (2H, br. s).

Preparation of 6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

Hydrochloric acid (4 M; 5 mL, 20 mmol) was added to a stirred solutionof N-(2,2-dimethoxyethyl)-3,3-dimethyl-3,4-dihydro-2H-pyrrol-5-aminehydroiodide (5.35 g, 16.3 mmol) in 1,4-dioxane (50 mL) at r.t. Theresulting mixture was heated at 90° C. for 3 h. The mixture was thencooled to r.t. and stirred under these conditions for 2.5 days beforebeing concentrated under reduced pressure to provide a dark brown tar.This mixture was dissolved in DCM and diluted with Et₂O. Aqueous ammonia(28-30%; 2.8 mL) was added to the stirring mixture. The layers wereseparated, and the organic layer was dried over MgSO₄, filtered, andconcentrated under reduced pressure to provide6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (2.32 g, 100%) as abrown oil. ¹H NMR (400 MHz, CDCl₃, 21° C.) 1.28 (6H, s), 2.70 (2H, s),3.69 (2H, s), 6.84 (1H, d), 7.03 (1H, d).

Example 23:(R)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide

(R)-Tetrahydrofuran-3-carboxylic acid (0.036 g, 0.31 mmol), HATU (0.118g, 0.31 mmol) and triethylamine (0.11 mL, 0.77 mmol) were stirredtogether in DMF (2 mL) under nitrogen for 20 minutes. Then(1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.100 g, 0.26 mmol; prepared according to Example 14 using5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoleprepared as described below) in DMF (1 mL) was added, and the mixturewas stirred for another 30 minutes. The reaction was concentrated underreduced pressure, and the mixture was purified by flash C18chromatography, elution gradient 20 to 60% MeCN in water containing 1%aqueous NH₄OH. Pure fractions were concentrated under reduced pressureto afford(R)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide(0.113 g, 90%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.)1.05-1.2 (1H, m), 1.20-1.38 (9H, sm), 1.79 (3H, br. d), 1.86-2.03 (3H,m), 2.56-2.63 (1H, m), 2.81-2.91 (3H, m), 3.52-3.78 (4H, m), 3.83 (1H,t), 3.95 (2H, s), 7.83 (1H, d), 7.99 (1H, s), 8.25 (1H, s), 8.34 (1H,s), 10.53 (1H, s). m/z: ES+ [M+H]+ 486.

An alternative procedure used to prepare5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(already described in Example 14, Intermediates) is described below:

Preparation of 3-iodo-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

NIS (1.646 g, 7.32 mmol) was added portionwise to5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (0.906 g, 6.65 mmol;prepared according to Example 14) in acetonitrile (40 mL) at r.t. undernitrogen. The resulting mixture was stirred at 23° C. for 18 h. Thereaction mixture was diluted with EtOAc (50 mL) and washed sequentiallywith water (40 mL), aqueous sodium thiosulfate (10 g in 30 mL), andsaturated aqueous sodium chloride (20 mL). The organic layer was driedover MgSO₄, filtered, and concentrated under reduced pressure to affordcrude product (1.59 g, 91%) as an orange oil. This oil was purified bydistillation under reduced pressure (0.12 mbar), with collection at ahead temperature of 140° C. Distillate collected in this manner afforded3-iodo-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (1.38 g, 79%)as a colourless liquid. Alternatively, the iodide was carried on to thenext step without distillation. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.30(6H, s), 2.63 (2H, s), 3.94 (2H, s), 7.47 (1H, s).

Preparation of5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

Isopropylmagnesium chloride lithium chloride complex in THF (1.3 M; 1.69mL, 2.20 mmol) was added dropwise over 10 minutes to3-iodo-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (0.444 g, 1.69mmol) in THF (5 mL) at −78° C. under nitrogen. The resulting mixture wasstirred at −78° C. for 45 minutes. Then2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.473 g, 2.54mmol) was added dropwise to the reaction mixture, keeping the internaltemperature at −78° C. Once addition was complete, the reaction mixturewas allowed to warm up to r.t. over 18 h. The reaction mixture was thenconcentrated under reduced pressure and diluted with EtOAc (40 mL). Theresulting mixture was washed sequentially with saturated aqueousammonium chloride (20 mL), water (20 mL), and saturated aqueous sodiumchloride (20 mL). The organic layer was dried over MgSO₄, filtered, andconcentrated under reduced pressure to afford5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(0.41 g, 93%) contaminated with ˜13 mol % of des-iodo starting materialbased on NMR analysis as a waxy solid. Trituration with heptane affordedpure5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(0.24 g, 55%) as a white solid.

Example 24:(S)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide

A solution of (S)-tetrahydrofuran-3-carboxylic acid (0.036 g, 0.31mmol), HATU (0.12 g, 0.31 mmol) and triethylamine (0.11 mL, 0.77 mmol)in DMF (2 mL) was stirred under nitrogen for 20 minutes. Then(1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.10 g, 0.26 mmol; prepared according to Example 14 using5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoleprepared as described in Example 23) in DMF (1 mL) was added, and theresulting mixture was stirred under these conditions for 30 minutes. Themixture was concentrated under reduced pressure, and the resultingresidue was purified by flash C18 chromatography, elution gradient 20 to60% MeCN in water containing 1% NH₄OH. Pure fractions were concentratedunder reduced pressure to afford(S)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide(0.10 g, 81%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.)1.05-1.16 (1H, m), 1.21-1.41 (9H, m), 1.72-1.83 (3H, m), 1.87-2.04 (3H,m), 2.57-2.66 (1H, m), 2.82-2.91 (3H, m), 3.54-3.77 (4H, m), 3.83 (1H,t), 3.95 (2H, s), 7.83 (1H, d), 7.99 (1H, s), 8.25 (1H, s), 8.35 (1H,s), 10.54 (1H, s). m/z: ES+ [M+H+] 486.

Example 25:(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide

Tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.12 mmol) andXantphos (0.13 g, 0.23 mmol) were added together in one portion to adegassed mixture of tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate(0.670 g, 2.76 mmol),3-(2-chloro-5-fluoropyridin-4-yl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(0.61 g, 2.3 mmol), cesium carbonate (1.88 g, 5.76 mmol), and1,4-dioxane (26 mL). The resulting bright yellow mixture was maintainedunder reflux conditions by immersion in an oil bath that had beenpreheated to 120° C. After 20 h the reaction was cooled, diluted with50% saturated aqueous sodium chloride, and extracted with ethyl acetate(2×). The combined organic layers were dried over sodium sulfate,filtered, and concentrated under reduced pressure to afford crudetert-butyl((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamateas a light yellow solid. Hydrochloric acid in dioxane (4 M; 10 mL, 40mmol) and DCM (5 mL) were added, resulting in a clear orange solutionthat rapidly became cloudy and yellow. Methanol (˜3 mL) was titratedinto the reaction until the mixture became mostly clear. After 15 minthe orange mixture was concentrated under reduced pressure to afford anorange solid. Pyridine (3.7 ml, 46 mmol) was added to this solid alongwith DCM (19 mL). A slight exotherm was noted, and the reaction wasimmersed in a water bath. Then acetic anhydride (0.43 mL, 4.6 mmol) wasadded dropwise. After another 10 min, another 200 μL of acetic anhydridewere added. After another 30 min, another 600 μL of anhydride and 6 mLof pyridine were added. The reaction was maintained under theseconditions for another 45 min and was then poured into saturated aqueoussodium bicarbonate and ethyl acetate. The layers were separated, and theaqueous layer was extracted with ethyl acetate. The combined organiclayers were dried over sodium sulfate, filtered, and concentrated underreduced pressure. The resulting orange residue was purified by flashsilica chromatography, elution gradient 50 to 100% EtOAc in hexanefollowed by 0 to 20% methanol in ethyl acetate, and pure fractions wereconcentrated under reduced pressure to afford(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide(0.89 g, 94%) as a faint yellow foam solid. ¹H NMR (DMSO-d₆, 27° C.):1.00-1.16 (1H, m), 1.22-1.40 (9H, m), 1.74-1.81 (6H, m), 1.83-1.94 (1H,m), 2.55-2.68 (1H, m), 2.93 (2H, s), 3.49-3.65 (1H, m), 3.94 (s, 2H),7.75 (1H, d), 7.88 (1H, d), 8.28 (1H, d), 8.30 (1H, d), 10.46 (1H, s).m/z: ES+ [M+H]+ 414.

Method 1: A slurry of Example 25 (381 mg) in EtOAc was stirred at r.t.for 18 h, then filtered and washed with cold EtOAc to afford(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide(149 mg) as a crystalline white solid known as Example 25 Form A.Method 2: Approximately 5 g of Example 25 were taken up in 1:1:1hexanes:DCM:acetone (˜20 mL) and then concentrated under reducedpressure to give a slightly translucent gel. This gel was then treatedwith a small amount of the same solvent (˜5 mL) and stirred vigorouslyfor 10 min until a homogeneous white mixture formed and no gel wasvisible. This mixture was filtered with a 30% acetone in hexane wash,and the precipitate was dried under vacuum at 50° C. to afford Example25 Form A as a white solid.

Crystals of Example 25 (Form A) were analyzed by XRPD and the resultsare tabulated below and are shown in FIG. 3. The XRPD of the solidconfirms that the solid contains Form A.

Example 25 Form A main peaks are shown in Table 2 below:

Peak 2θ Intensity % 1 8.8 100.0 (vs)  2 10.1 18.0 (s) 3 11.5 35.8 (vs) 418.9 23.5 (s) 5 20.0 28.7 (vs) 6 20.5 28.1 (vs) 7 21.8 28.3 (vs) 8 22.825.8 (vs) 9 23.9 23.9 (s) 10 25.2 23.9 (s)

According to the present invention there is provided a crystalline form,Form A, which has an X-ray powder diffraction pattern with specificpeaks at about 2-theta=8.8, 10.1, 11.5, 18.9, 20.0, 20.5, 21.8, 22.8,23.9 and 25.2°.

Crystals obtained according to Methods 1 and 2 (Form A) were analyzed bythermal techniques. DSC analysis indicated that Form A melts with anonset point at 1940 and a peak at 1970. TGA indicated that Form Aexhibits a mass loss of about 1.4% upon heating from 22 to 100° C. Arepresentative DSC/TGA thermogram is shown in FIG. 4.

An alternative procedure for making(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamideis described in Example 86

Procedures used to prepare the starting materials tert-butyl((1R,3S)-3-carbamoylcyclohexyl)carbamate and3-(2-chloro-5-fluoropyridin-4-yl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoleare described below:

Preparation of3-(2-chloro-5-fluoropyridin-4-yl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

2-Chloro-5-fluoro-4-iodopyridine (1.00 g, 3.88 mmol),5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(1.53 g, 5.83 mmol; prepared according to Example 23), 2nd GenerationXPhos Precatalyst (0.31 g, 0.39 mmol) and dibasic potassium phosphate(2.03 g, 11.65 mmol) were dissolved in degassed dioxane (10 mL) andwater (2 mL) at 21° C. The reaction mixture was stirred at 80° C. for 3h, and then the mixture was cooled, diluted with EtOAc (30 mL), andwashed with water (10 mL). The organic layer was concentrated underreduced pressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 50% EtOAc in heptane. Purefractions were concentrated under reduced pressure to afford3-(2-chloro-5-fluoropyridin-4-yl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(1.00 g, 97%) as a white solid. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.36(6H, s), 2.95 (2H, d), 3.97 (2H, s), 7.31 (1H, d), 7.94 (1H, d), 8.20(1H, d). m/z: ES+ [M+H]+ 266.

Preparation of (cis)-benzyl3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate

Benzyl bromide (12.4 mL, 104 mmol) was added dropwise as a solution inDMF (10 mL) to a degassed mixture ofcis-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (19.5 g,80.0 mmol, prepared according to Example 2 Intermediates), cesiumcarbonate (33.9 g, 104 mmol), and DMF (80 mL) at 0° C. The ice bath wasremoved, and the reaction was stirred under these conditions for 18 h.The mixture was then diluted with an equal volume of ethyl acetate andfiltered with an ethyl acetate wash. The organic layer was washed with50% saturated aqueous sodium chloride (3×) and then saturated aqueoussodium chloride. The organic layer was then dried over sodium sulfate,filtered, and concentrated under reduced pressure. The resulting lightyellow oil was purified by flash silica chromatography, elution gradient0 to 30% ethyl acetate in hexanes, to afford cis-benzyl3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate (25.4 g, 95%) as aclear colorless oil that solidified to a white solid on standing. ¹H NMR(DMSO-d₆, 27° C.) 0.98-1.34 (4H, m), 1.38 (9H, s), 1.67-1.78 (2H, m),1.84 (1H, d), 1.99 (1H, d), 2.35-2.49 (1H, m), 3.17-3.31 (1H, s), 5.09(2H, s), 6.76 (1H, d), 7.30-7.42 (5H, m). m/z: ES+ [M+Na]+ 356.

Preparation of (1S,3R)-benzyl3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate and (1R,3S)-benzyl3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate

Cis-benzyl 3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate (25.4 g,76.2 mmol) was resolved by preparative SFC conditions (Column: LuxAmylose-2, 5 μm, 21.2 mm diameter, 250 mm length, 40° C. columntemperature, 80 mL/min flow rate), eluting with 10% isopropanol in CO₂,to afford (1S,3R)-benzyl3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate (11.5 g, 45%) as awhite solid and (1R,3S)-benzyl3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate (11.5 g, 45%) as awhite solid.

(1S,3R)-benzyl 3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate

¹H NMR (DMSO-d₆, 27° C.) 0.96-1.34 (4H, m), 1.37 (9H, s), 1.68-1.88 (3H,m), 1.98 (1H, d), 2.37-2.48 (1H, m), 3.16-3.32 (1H, m), 5.09 (2H, s),6.59-6.84 (1H, m), 7.26-7.50 (5H, m). m/z: ES+ [M+Na]+ 356.

Optical Rotation:

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 25° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: DCM

[α]=+21.9

(1R,3S)-benzyl 3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate

¹H NMR (DMSO-d₆, 27° C.) 0.95-1.34 (4H, m), 1.37 (9H, s), 1.68-1.78 (2H,m), 1.84 (1H, d), 1.98 (1H, d), 2.36-2.48 (1H, m), 3.17-3.34 (1H, m),5.09 (2H, s), 6.76 (1H, d), 7.30-7.41 (5H, m). m/z: ES+ [M+Na]+ 356.

Optical Rotation:

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 25° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: DCM

[α]=−28.3

Analytical SFC Conditions:

Column: Lux Amylose-2

Column Dimensions: 5 μm, 4.6 mm diameter, 50 mm length,

Column Temperature: 40° C.

Mobile Phase A: CO₂ (100%)

Mobile Phase B: Isopropanol

Gradient: Isocratic 10% Mobile Phase B

Flow Rate: 1 mL/min over 5 min

Retention Time:

0.66 min, (1S,3R)-benzyl3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate

0.96 min, (1R,3S)-benzyl3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate

e.e.

>98%, (1S,3R)-benzyl3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate

97.5%, (1R,3S)-benzyl3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate

An alternative procedure for the preparation of(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid(already described in Example 2, Intermediates) is described below:

A degassed mixture of (1S,3R)-benzyl3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate (11.5 g, 34.6mmol), palladium on carbon (10 wt %; 3.68 g, 34.5 mmol), and methanol(86 mL) was subjected to a hydrogen atmosphere (1 atm, balloon). After18 h, the mixture was filtered with a methanol wash. The filtrate wasconcentrated to a slightly turbid faint gray oil. This oil was taken upin ethyl acetate, dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The resulting white oily solid was heated undervacuum until all bubbling from solvent evaporation stopped. Cooling tor.t. afforded(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (8.4 g,99%) as a white solid (See Example 2, Intermediates, forcharacterization).

Optical Rotation:

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 25° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: DMSO

[α]=+44.6

Preparation of tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate

Carbonyl diimidazole (6.44 g, 39.74 mmol) was added to a solution of(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (3.22g, 13.3 mmol) in DMF (30 mL) at 40° C. The resulting mixture was stirredat 40° C. for 4 h. The reaction mixture was then cooled to 0° C., andammonium acetate (7.15 g, 92.7 mmol) was added in one portion withvigorous stirring. This was followed by gas evolution and generation ofa foam. A small amount (˜2 mL) of DCM was added along the sides of theflask to break apart the foam and prevent it from reaching the flaskopening. Gradually this foam was reabsorbed by the reaction mixture,which was allowed to warm to r.t. overnight. After a total of 18 h underthese conditions, the reaction mixture was poured into ice water, andthe resulting mixture was stirred under these conditions for 5 minbefore being filtered with a water wash. The resulting precipitate wasdried under vacuum at 80° C. for 2 h before being cooled to r.t. Vacuumdrying was then continued for 18 h to afford tert-butyl((1R,3S)-3-carbamoylcyclohexyl)carbamate (2.76 g, 86%) as a white fluffysolid. ¹H NMR (DMSO-d₆, 27° C.) 0.99-1.31 (4H, m), 1.38 (9H, s),1.58-1.85 (4H, m), 2.06-2.19 (1H, m), 3.14-3.26 (1H, m), 6.63 (1H, brs), 6.73 (1H, d), 7.17 (1H, br s). m/z: ES+ [M+Na]+ 265.

Optical Rotation:

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 25° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: Methanol

[α]=+51.3

Example 26:cis-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide

Tetrabutylammonium fluoride in THF (1 M; 0.154 mL, 0.15 mmol) was addedto a stirred solution ofcis-3-((tert-butyldimethylsilyl)oxy)-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclobutanecarboxamide(68 mg, 0.15 mmol) in THF (3 mL) at r.t. under a nitrogen atmosphere.The reaction mixture was stirred under these conditions for 2 h and thenpurified using an SCX column, eluting sequentially with DCM, MeOH, and1% NH₃ in MeOH. Product fractions were concentrated under reducedpressure. The resulting residue was purified by preparative HPLC (WatersXBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length),using decreasingly polar mixtures of water (containing 1% NH₃) and MeCNas eluents to affordcis-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide(43 mg, 85%). ¹H NMR (500 MHz, DMSO-d₆, 30° C.) 1.30 (6H, s), 2.05 (2H,qd), 2.28-2.43 (2H, m), 2.71-2.85 (1H, m), 2.95 (2H, s), 3.91 (2H, s),3.98 (1H, q), 5.13 (1H, d), 7.17-7.26 (1H, m), 7.98 (1H, s), 8.21 (1H,dd), 8.25 (1H, s), 10.30 (1H, s). m/z: ES+ [M+H]+ 327.

Procedures used to prepare the starting materialcis-3-((tert-butyldimethylsilyl)oxy)-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclobutanecarboxamideare described below:

Preparation ofcis-3-((tert-butyldimethylsilyl)oxy)-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclobutanecarboxamide

Cis-N-(4-bromopyridin-2-yl)-3-((tert-butyldimethylsilyl)oxy)cyclobutanecarboxamide(365 mg, 0.800 mmol; prepared according to Example 6),5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(185 mg, 0.700 mmol; prepared according to Example 23), potassiumphosphate (446 mg, 2.10 mmol) and 2nd Generation XPhos Precatalyst (55mg, 0.070 mmol) were suspended in 1,4-dioxane (4 mL) and water (0.80 mL)at r.t. The resulting mixture was degassed, purged with nitrogen, andthen heated at 85° C. for 18 h. The reaction mixture was cooled to r.t.and partitioned between EtOAc (50 mL) and water (25 mL). The layers wereseparated, and the aqueous layer was extracted with EtOAc (2×50 mL) andDCM (50 mL). The combined organic layers were dried over MgSO₄,filtered, and concentrated under reduced pressure. The resulting orangegum was purified by flash silica chromatography, eluting with 0 to 40%EtOAc in heptane. Product fractions were concentrated under reducedpressure to affordcis-3-((tert-butyldimethylsilyl)oxy)-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclobutanecarboxamide(68 mg, 22%) as a colourless crystalline solid. ¹H NMR (400 MHz, CDCl₃,22° C.) 0.06 (6H, s), 0.89 (9H, s), 1.36 (6H, s), 2.22-2.38 (2H, m),2.49-2.67 (3H, m), 3.02 (2H, s), 3.93 (2H, s), 4.15-4.35 (1H, m), 7.11(1H, dd), 7.82 (1H, s), 7.92 (1H, s), 8.17 (1H, d), 8.30 (1H, s). m/z:ES+ [M+H]+ 441.

Example 27:cis-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide

Tetrabutyammonium fluoride in THF (1 M; 0.21 mL, 0.21 mmol) was added toa stirred solution ofcis-3-((tert-butyldimethylsilyl)oxy)-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclobutanecarboxamide(101 mg, 0.210 mmol) in THF (3 mL) at r.t. under a nitrogen atmosphere.The resulting solution was stirred under these conditions for 18 h. Thereaction mixture purified using an SCX column, eluting sequentially withDCM, MeOH, and 1% NH₃ in MeOH. Product fractions were concentrated underreduced pressure. The resulting residue was purified by preparative HPLC(Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mmlength), using decreasingly polar mixtures of water (containing 1% NH₃)and MeCN as eluents. Product fractions were concentrated under reducedpressure, and the resulting residue was further purified by preparativeHPLC (Waters SunFire column, 5μ silica, 30 mm diameter, 100 mm length),using decreasingly polar mixtures of water (containing 0.1% formic acid)and MeCN as eluents. Fractions containing the desired compound wereconcentrated under reduced pressure to affordcis-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide (35 mg, 45%). ¹H NMR (500 MHz, DMSO-d₆, 30° C.) 1.29 (6H,s), 2.04 (2H, qd), 2.37 (2H, qd), 2.77 (1H, ddd), 2.92 (2H, s), 3.96(2H, s), 3.96-4.02 (1H, m), 5.14 (1H, d), 8.02 (1H, s), 8.29 (1H, s),8.34 (1H, d), 10.51 (1H, s). m/z: ES+ [M+H]+ 361.

Procedures for preparing the starting materialcis-3-((tert-butyldimethylsilyl)oxy)-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclobutanecarboxamideare described below.

Preparation ofcis-3-((tert-butyldimethylsilyl)oxy)-N-(5-chloro-4-iodopyridin-2-yl)cyclobutanecarboxamide

T₃P in ethyl acetate (50 wt %; 2.85 mL, 4.79 mmol) was added to astirred solution of 5-chloro-4-iodopyridin-2-amine (610 mg, 2.40 mmol;prepared according to Example 2),cis-3-((tert-butyldimethylsilyl)oxy)cyclobutanecarboxylic acid (552 mg,2.40 mmol; prepared according to Example 4) and pyridine (0.78 mL, 9.6mmol) in EtOAc (10 mL) at r.t. The resulting solution was stirred atr.t. for 18 h. The reaction was quenched by the addition of saturatedaqueous ammonium chloride (30 mL). The layers were separated and theaqueous layer was extracted with EtOAc (3×50 mL). The combined organiclayers were dried over MgSO₄, filtered, and concentrated under reducedpressure to affordcis-3-((tert-butyldimethylsilyl)oxy)-N-(5-chloro-4-iodopyridin-2-yl)cyclobutanecarboxamide (1.07 g, 96%) as a cream-colored crystalline solid. ¹H NMR(400 MHz, CDCl₃, 21° C.) 0.06 (6H, s), 0.89 (9H, s), 2.23-2.35 (2H, m),2.47-2.64 (3H, m), 4.17-4.32 (1H, m), 7.95 (1H, bs), 8.18 (1H, s), 8.86(1H, s). m/z: ES+ [M+H]+ 467.

Preparation ofcis-3-((tert-butyldimethylsilyl)oxy)-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclobutanecarboxamide

Cis-3-((tert-butyldimethylsilyl)oxy)-N-(5-chloro-4-iodopyridin-2-yl)cyclobutanecarboxamide(461 mg, 0.840 mmol),5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(200 mg, 0.76 mmol; prepared according to Example 23), potassiumphosphate (486 mg, 2.29 mmol) and 2nd Generation XPhos Precatalyst (60.0mg, 0.08 mmol) were suspended in 1,4-dioxane and water at r.t. Theresulting mixture was degassed, purged with nitrogen, and heated at 85°C. overnight. The reaction was cooled to r.t. and partitioned betweenEtOAc (50 mL) and water (25 mL). The layers were separated, and theaqueous layer was extracted with EtOAc (3×50 mL). The combined organiclayers were dried over MgSO₄, filtered, and concentrated under reducedpressure. The resulting orange gum was purified by flash silicachromatography, eluting with 0 to 40% EtOAc in heptane. Productfractions were evaporated to dryness to affordcis-3-((tert-butyldimethylsilyl)oxy)-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclobutanecarboxamide(101 mg, 28%) as a colourless crystalline solid. ¹H NMR (400 MHz, CDCl₃,21° C.) 0.06 (6H, s), 0.89 (9H, s), 1.35 (6H, s), 2.24-2.45 (2H, m),2.5-2.74 (3H, m), 2.98 (2H, s), 3.96 (2H, s), 4.18-4.24 (1H, m), 7.77(1H, s), 8.14 (1H, s), 8.23 (1H, s), 8.29 (1H, s). m/z: ES+ [M+H]+ 475.

Example 28:(1S,3R)-3-acetamido-N-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)cyclohexanecarboxamide

A flask charged with(1S,3R)-3-acetamido-N-(6-chloropyrimidin-4-yl)cyclohexanecarboxamide(100 mg, 0.34 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(84 mg, 0.34 mmol),dichloro[1,1′-bis(di-tertbutylphosphino)ferrocene]palladium(II) (11 mg,0.020 mmol) and potassium phosphate (215 mg, 1.01 mmol) was evacuatedand back filled with nitrogen (3×). Degassed 1,4-dioxane (1 mL) followedby water (0.2 mL) were added, and the mixture was heated to 90° C. andmaintained under these conditions for 18 h. The reaction was thenconcentrated under reduced pressure, and the resulting residue waspartitioned between saturated aqueous sodium bicarbonate (20 mL) andethyl acetate (20 mL). The layers were separated, and the aqueous layerwas extracted with ethyl acetate (2×20 mL). The combined organic layerswere washed with saturated aqueous sodium chloride (20 mL), dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresulting residue was purified by column chromatography on basicalumina, elution gradient 0 to 100% (10% MeOH in EtOAc) in heptane toafford(1S,3R)-3-acetamido-N-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)cyclohexanecarboxamide(55 mg, 43%) as a tan solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.) 1.01-1.38(4H, m), 1.76-2.02 (11H, m), 2.62-2.69 (1H, m), 3.10 (2H, t), 3.52-3.61(1H, m), 4.13 (2H, t), 7.74 (1H, d), 7.96 (1H, s), 8.21 (1H, d), 8.75(1H, d), 10.72 (1H, s). m/z: ES+ [M+H]+ 383.

Procedures used to prepare the starting material(1S,3R)-3-acetamido-N-(6-chloropyrimidin-4-yl)cyclohexanecarboxamide aredescribed below:

Preparation of tert-butyl((1R,3S)-3-((6-chloropyrimidin-4-yl)carbamoyl)cyclohexyl)carbamate

1-Chloro-N,N,2-trimethylpropenylamine (3.26 mL, 24.7 mmol) was added toa solution of(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (5.00g, 20.6 mmol; prepared as in Example 2) in DCM (50 mL) and the resultingmixture stirred for 90 min at r.t. Then 6-chloropyrimidin-4-amine (2.66g, 20.6 mmol) and pyridine (2.0 mL, 25 mmol) were added, and theresulting mixture was stirred under these conditions for 18 h. Thereaction was quenched with saturated aqueous sodium bicarbonate (50 mL),and the layers were separated. The aqueous layer was extracted with DCM(2×50 mL), and the combined organic layers were washed with saturatedaqueous sodium chloride and dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby flash silica chromatography, eluting with 0 to 100% (10% methanol inethyl acetate) in heptane. Product fractions were combined andconcentrated under reduced pressure to give tert-butyl((1R,3S)-3-((6-chloropyrimidin-4-yl)carbamoyl)cyclohexyl)carbamate (1.0g, 14%) as a white solid. m/z: ES− [M−H]− 353.

Preparation of(1S,3R)-3-amino-N-(6-chloropyrimidin-4-yl)cyclohexanecarboxamidedihydrochloride

Hydrochloric acid in dioxane (4 M; 0.655 mL, 21.6 mmol) was added to asolution of tert-butyl((1R,3S)-3-((6-chloropyrimidin-4-yl)carbamoyl)cyclohexyl)carbamate (900mg, 2.54 mmol) in methanol (5 mL), and the resulting mixture was stirredovernight at r.t. The mixture was then diluted with toluene (10 mL) andconcentrated under reduced pressure to give(1S,3R)-3-amino-N-(6-chloropyrimidin-4-yl)cyclohexanecarboxamidedihydrochloride (880 mg, 106%) as a white solid which was used directlyin the next stage without further purification.

Preparation of(1S,3R)-3-acetamido-N-(6-chloropyrimidin-4-yl)cyclohexanecarboxamide

Acetyl chloride (0.11 mL, 1.5 mmol) was added to a mixture of(1S,3R)-3-amino-N-(6-chloropyrimidin-4-yl)cyclohexanecarboxamide (0.217g, 0.85 mmol), pyridine (0.69 mL, 8.5 mmol), and DCM (7.7 mL) at 0° C.After 30 min, another 200 μL of acetyl chloride were added. This wasagain repeated after another 30 min a final time. The reaction was thenquenched with saturated aqueous sodium bicarbonate and extracted withethyl acetate (2×). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Theresulting residue was purified by flash silica chromatography, elutiongradient 10 to 100% ethyl acetate in hexane then 0 to 15% methanol inethyl acetate) to afford(1S,3R)-3-acetamido-N-(6-chloropyrimidin-4-yl)cyclohexanecarboxamide(0.22 g, 87%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) 0.99-1.16(1H, m), 1.18-1.38 (3H, m), 1.72-1.84 (6H, m), 1.85-1.97 (m, 1H),2.58-2.73 (1H, m) 3.50-3.64 (1H, m) 7.76 (1H, d) 8.12 (1H, d) 8.74 (1H,d) 11.18 (1H, s). m/z: ES+ [M+H]+ 297.

Example 29:trans-3-hydroxy-N-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)cyclobutanecarboxamide

Hydrochloric acid in dioxane (4 M; 0.085 mL, 0.34 mmol) was added to asolution oftrans-3-((tert-butyldimethylsilyl)oxy)-N-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)cyclobutanecarboxamide(29 mg, 0.070 mmol) in MeOH (1 mL), and the resulting mixture wasstirred at r.t. for 2 h. The mixture was concentrated under reducedpressure, and the resulting residue was purified by preparative HPLC(Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 100 mmlength), using decreasingly polar mixtures of water (containing 1% NH₃)and MeCN as eluents. Fractions containing the desired compound wereconcentrated under reduced pressure to affordtrans-3-hydroxy-N-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)cyclobutanecarboxamide(10 mg, 47%) as a white solid. ¹H NMR (400 MHz, CD₃OD, 30° C.) 1.93-2.05(2H, m), 2.07-2.18 (2H, m), 2.26 (2H, m), 2.60 (2H, m), 3.17-3.28 (3H,m), 4.21 (2H, t), 4.49 (1H, p), 8.06 (1H, s), 8.33 (1H, d), 8.71 (1H,d). m/z: ES+ [M+H]+ 314.

Procedures for preparing the starting materialtrans-3-((tert-butyldimethylsilyl)oxy)-N-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)cyclobutanecarboxamideare described below:

Preparation oftrans-3-((tert-butyldimethylsilyl)oxy)-N-(6-chloropyrimidin-4-yl)cyclobutanecarboxamide

1-Chloro-N,N,2-trimethylpropenylamine (0.383 mL, 2.89 mmol) was added toa solution oftrans-3-((tert-butyldimethylsilyl)oxy)cyclobutanecarboxylic acid (0.667g, 2.89 mmol; prepared according to Example 4, substitutingtrans-3-hydroxycyclobutanecarboxylic acid forcis-3-hydroxycyclobutanecarboxylic acid) in DCM (10 mL) and theresulting mixture stirred at r.t. for 1.5 h. 6-Chloropyrimidin-4-amine(0.25 g, 1.93 mmol) and pyridine (0.23 mL, 2.9 mmol) were then added andthe mixture was stirred at r.t. overnight. The reaction was quenchedwith saturated aqueous sodium bicarbonate (50 mL), and the layersseparated. The aqueous layer was extracted with DCM (2×50 mL). Thecombined organic layers were washed with saturated aqueous sodiumchloride, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 100% ethyl acetate in heptane. Thefractions containing product were combined, concentrated under reducedpressure to givetrans-3-((tert-butyldimethylsilyl)oxy)-N-(6-chloropyrimidin-4-yl)cyclobutanecarboxamide(0.230 g, 35%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.) 0.00(6H, s), 0.84 (9H, s), 2.10 (2H, m), 2.38-2.45 (2H, m), 3.21 (1H, t),4.44 (1H, p), 8.14 (1H, s), 8.71 (1H, s), 11.13 (1H, s br). m/z: ES+[M+H]+ 342.

Preparation oftrans-3-((tert-butyldimethylsilyl)oxy)-N-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)cyclobutanecarboxamide

Trans-3-((tert-butyldimethylsilyl)oxy)-N-(6-chloropyrimidin-4-yl)cyclobutanecarboxamide(100 mg, 0.29 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(73 mg, 0.29 mmol),dichloro-[1,1′-bis(di-tertbutylphosphino)ferrocene]palladium(II) (9.5mg, 0.01 mmol) and potassium phosphate (186 mg, 0.88 mmol) were chargedto a flask, and the flask was evacuated and back filled with nitrogen(3×). Degassed 1,4-dioxane (1 mL) was then added, and the mixture washeated to 90° C. and maintained under these conditions for 2 h. Thereaction was concentrated under reduced pressure, and the resultingresidue was partitioned between saturated aqueous sodium bicarbonate (20mL) and ethyl acetate (20 mL). The layers were separated, and theaqueous layer was extracted with ethyl acetate (2×20 mL). The combinedorganic layers were washed with saturated aqueous sodium chloride (20mL), dried over sodium sulfate, filtered, and concentrated under reducedpressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 100% EtOAc in heptane to givetrans-3-((tert-butyldimethylsilyl)oxy)-N-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)cyclobutanecarboxamide(29 mg, 23%) as a white solid. ¹H NMR (400 MHz, CDCl₃, 30° C.) 0.00 (6H,s), 0.89 (9H, s), 1.91-1.99 (2H, m), 2.08 (2H, m), 2.29 (2H, m), 2.63(2H, m), 3.01-3.10 (1H, m), 3.23 (2H, t), 4.21 (2H, t), 4.52-4.63 (1H,m), 8.08 (1H, s), 8.31 (1H, d), 8.43 (1H, s br), 8.73 (1H, d). m/z: ES+[M+H]+ 428.

Example 30:(1S,3R)-3-acetamido-N-(6-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)cyclohexanecarboxamide

Acetic anhydride (0.038 mL, 0.41 mmol) was added dropwise to crude(1S,3R)-3-amino-N-(6-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)cyclohexanecarboxamidehydrochloride (0.120 g, 0.308 mmol), 4-dimethylaminopyridine (2.07 mg,0.02 mmol), and triethylamine (0.15 mL, 1.1 mmol) in DCM (2 mL) at r.t.under nitrogen. The resulting solution was stirred at r.t. for 4 h. Thereaction mixture was then quenched with saturated aqueous NH₄Cl (10 mL),extracted with DCM (2×10 mL), and the combined organic layers were driedover MgSO₄, filtered, and concentrated under reduced pressure. Theresulting residue was purified by preparative HPLC (Waters XBridge PrepC18 OBD column, 5a silica, 30 mm diameter, 100 mm length), usingdecreasingly polar mixtures of water (containing 1% NH₃) and MeCN aseluents. Fractions containing the desired compound were concentratedunder reduced pressure to afford(1S,3R)-3-acetamido-N-(6-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)cyclohexanecarboxamide(0.066 g, 55%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆, 30° C.)1.02-1.12 (1H, m), 1.25-1.37 (9H, m), 1.76-1.88 (6H, m), 1.90-1.96 (1H,m), 2.61-2.67 (1H, m), 2.95 (2H, s), 3.54-3.61 (1H, m), 3.92 (2H, s),7.76 (1H, br d), 8.03 (1H, d), 8.15 (1H, d), 8.73 (1H, dd), 10.75 (1H, sbr). m/z: ES+ [M+H]+ 397.

Procedures for preparing the starting material(1S,3R)-3-amino-N-(6-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)cyclohexanecarboxamidehydrochloride are described below:

Preparation of tert-butyl((1R,3S)-3-((6-bromopyrimidin-4-yl)carbamoyl)cyclohexyl) carbamate

1-Chloro-N,N,2-trimethylpropenylamine (0.46 mL, 3.5 mmol) was addeddropwsie to a solution of(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (699mg, 2.87 mmol; prepared according to Example 2) in DCM (10 mL) at 0° C.under nitrogen. The resulting solution was stirred at 0° C. for 1.5 h.6-Bromopyrimidin-4-amine (400 mg, 2.30 mmol) and pyridine (0.28 mL, 3.5mmol) were then added, and the reaction mixture was stirred at r.t.overnight. The crude reaction mixture was concentrated under reducedpressure. To the resulting solid, DCM was then added. The resultingmixture was then filtered, and the resulting precipitate was purified byflash silica chromatography, elution gradient 0 to 2% MeOH in DCM. Purefractions were concentrated under reduced pressure to afford tert-butyl((1R,3S)-3-((6-bromopyrimidin-4-yl)carbamoyl)cyclohexyl)carbamate (605mg, 66%) as a white solid. m/z: ES+ [M+H]+ 399

Preparation of tert-butyl((1R,3S)-3-((6-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)carbamoyl)cyclohexyl)carbamate

2nd Generation XPhos Precatalyst (0.039 g, 0.050 mmol) was added to adegassed mixture of5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(0.18 g, 0.60 mmol; prepared according to Example 23), tert-butyl((1R,3S)-3-((6-bromopyrimidin-4-yl)carbamoyl)cyclohexyl)carbamate (0.20g, 0.50 mmol) and potassium phosphate, tribasic, (0.262 g, 1.50 mmol) in1,4-dioxane (10 mL) and, water (2 mL). The mixture was degassed and wasstirred at 90° C. for 2 h under nitrogen. The reaction mixture was thenconcentrated under reduced pressure, and the resulting residue was takenup in water (20 mL). The resulting mixture was extracted sequentiallywith EtOAc (2×20 mL) and DCM (20 mL). The combined organic layers weredried over MgSO₄, filtered, and concentrated under reduced pressure. Theresulting residue was purified by flash silica chromatography, elutiongradient 0 to 100% EtOAc in heptane. Pure fractions were concentratedunder reduced pressure to afford tert-butyl((1R,3S)-3-((6-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)carbamoyl)cyclohexyl)carbamate(0.18 g, 79%) as a cream-colored solid. ¹H NMR (400 MHz, CDCl₃, 30° C.)1.06-1.13 (1H, m), 1.35 (6H, s), 1.41-1.50 (12H, m), 1.87-1.96 (3H, m),2.26-2.37 (1H, d), 2.38-2.44 (1H, m), 3.04 (2H, s), 3.44-3.58 (1H, m)3.93 (2H, s), 4.44-4.52 (1H, m), 8.00 (1H, br s), 8.13 (1H, s), 8.18(1H, d), 8.72 (1H, dm/z: ES+ [M+H]+ 455.

Preparation of(1S,3R)-3-amino-N-(6-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)cyclohexanecarboxamidehydrochloride

Tert-butyl((1R,3S)-3-((6-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)carbamoyl)cyclohexyl)carbamate(0.160 g, 0.35 mmol) and hydrochloric acid in dioxane (4 M; 0.71 mL, 2.8mmol) were dissolved in methanol (2 mL) at r.t. under air. The resultingsolution was stirred at r.t. for 16 h. The reaction mixture wasconcentrated under reduced pressure, and the resulting crude(1S,3R)-3-amino-N-(6-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)cyclohexanecarboxamidehydrochloride (0.120 g, 88%) was carried on to the next step withoutfurther purification. m/z: ES+ [M+H]+ 355.

Example 31:(1S,3R)—N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(2-cyanoacetamido)cyclohexanecarboxamide

HATU (140 mg, 0.37 mmol) was added to a solution of(1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamidedihydrochloride (150 mg, 0.34 mmol; prepared according to Example 2),2-cyanoacetic acid (31.4 mg, 0.37 mmol), DIPEA (0.18 mL, 1.0 mmol) andDMF (1.2 mL). The reaction was stirred at r.t. for 3 h. The reaction wasdiluted with EtOAc and washed with saturated NaHCO₃ and saturatedaqueous sodium chloride. The organic layer was dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by flash silica chromatography, eluting with 80 to100% EtOAc in hexane, to afford(1S,3R)—N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(2-cyanoacetamido)cyclohexanecarboxamide(51 mg, 35%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.04-1.19 (1H, m), 1.21-1.39 (3H, m), 1.73-1.88 (5H, m), 1.93 (1H, brd), 1.99-2.10 (2H, m), 2.56-2.68 (1H, m), 2.80 (2H, t), 3.52-3.64 (3H,m), 4.14 (2H, t), 7.76 (1H, s), 8.14 (1H, s), 8.19 (1H, d), 8.38 (1H,s), 10.59 (1H, s). m/z: ES+ [M+H]+ 441.

Optical Rotation:

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 20° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: DMSO

[α]=+76.3

Example 31a: tert-butyl((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate

1-Chloro-N,N,2-trimethylprop-1-en-1-amine (0.344 g, 2.57 mmol) was addeddropwise to a stirred solution of(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (0.611g, 2.51 mmol; prepared according to Example 2) in DCM (12 mL) at 0° C.The resulting mixture was stirred at 0° C. for 1.5 h. Then a solution of5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine(0.50 g, 2.0 mmol; prepared according to Example 2) and pyridine (0.65mL, 8.0 mmol) in DCM (18 mL) was added dropwise. The colorless reactionmixture became yellow. The ice bath was removed, and the reaction wasmaintained under these conditions for 18 h. This same reaction was thenrepeated as follows: 1-Chloro-N,N,2-trimethylprop-1-en-1-amine (1.032 g,7.72 mmol) was added dropwise to a stirred solution of(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (1.8 g,7.5 mmol) in DCM (30 mL) at 0° C. The resulting mixture was stirred at0° C. for 1.5 h. Then a solution of5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine(1.5 g, 6.0 mmol) and pyridine (2.0 mL, 24 mmol) in DCM (50 mL) wasadded dropwise. The colorless reaction mixture became yellow. The icebath was removed, and the reaction was maintained under these conditionsfor 18 h. Both reactions were then combined and diluted with MeOH (10mL) to dissolve precipitates. The resulting solution was washed withsaturated aqueous sodium chloride, and the organic layer dried overNa₂SO₄, filtered, and concentrated under reduced pressure to minimumvolume. The resulting solution flash silica chromatography, elutiongradient 50 to 80% ethyl acetate in hexanes, to afford tert-butyl((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(2.6 g, 68%) as a solid. ¹H NMR (300 MHz, CDCl₃, 27° C.) 1.04-1.21 (1H,m), 1.38-1.52 (12H, m), 1.87-2.19 (7H, m), 2.31 (1H, br d), 2.36-2.49(m, 1H), 2.95 (2H, t), 3.45-3.61 (m, 1H), 4.24 (2H, t), 4.34-4.52 (1H,m), 7.92 (s, 1H). m/z (ES+), [M+H]+=474.

Example 31b:(1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Hydrochloric acid in dioxane (4 M; 3.2 mL, 13 mmol) was added to astirred suspension of tert-butyl((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(1 g, 2.11 mmol) in MeOH (4 mL) and DCM (4 mL). The reaction suspensionturned into a clear solution. The reaction was stirred at r.t. for 2 hand then concentrated under reduced pressure to1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamideisolated as the dihydrochloride salt (0.91 g, 97%) as a white solid. ¹HNMR (300 MHz, DMSO-d₆, 27° C.) 1.12-1.39 (3H, m), 1.50 (1H, q),1.77-1.90 (4H, m), 1.90-2.10 (4H, m), 2.57-2.69 (1H, m), 2.81 (2H, t),2.95-3.09 (1H, m), 4.14 (2H, t), 7.77 (1H, s), 7.99-8.21 (4H, m), 8.39(1H, s), 10.67 (1H, s). Additional HCl protons under a broad singlet at5.61 ppm. m/z (ES+), [M+H]+=374.

Example 32:(1S,3R)—N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide

HATU (140 mg, 0.37 mmol) was added to a solution of(1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamidedihydorochloride (150 mg, 0.34 mmol; prepared according to Example 31b),1-hydroxycyclopropanecarboxylic acid (34 mg, 0.34 mmol), DIPEA (0.18 mL,1.0 mmol) and DMF (1.2 mL). The reaction was stirred at r.t. for 3 h.The reaction was diluted with EtOAc and washed with saturated aqueousNaHCO₃ and saturated aqueous sodium chloride. The organic layer wasdried over sodium sulfate, filtered and concentrated under reducedpressure. The resulting residue was purified by flash silicachromatography elution gradient 80 to 100% EtOAc in hexane, to afford(1S,3R)—N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide(61 mg, 40%) as a white solid. ¹H NMR (300 MHz, CDCl₃, 27° C.) 1.00-1.09(m, 2H), 1.19-1.31 (1H, m), 1.34-1.40 (2H, m), 1.42-1.59 (3H, m),1.88-2.17 (7H, m), 2.30 (1H, br d), 2.44-2.58 (1H, m), 2.83 (1H, s),2.90-2.99 (2H, m), 3.83-3.95 (1H, m), 4.24 (2H, t), 6.83 (1H, d), 7.94(1H, s), 8.19 (1H, s), 8.27 (1H, s), 8.46 (1H, br s). m/z: ES+ [M+H]+458.

Optical Rotation:

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 20° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: DMSO

[α]=+105.4

Example 33:(R)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide

HATU (140 mg, 0.37 mmol) was added to a solution of(1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamidedihydrochloride (150 mg, 0.34 mmol; prepared according to Example 31b),(R)-tetrahydrofuran-3-carboxylic acid (43 mg, 0.37 mmol), DIPEA (0.18mL, 1.0 mmol) and DMF (1.2 mL). The reaction was stirred at r.t. for 3h. The reaction was diluted with EtOAc and washed with saturated aqueoussodium hydrogencarbonate and saturated aqueous sodium chloride. Theorganic layer was dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The resulting residue was purified by flashsilica chromatography, elution gradient 80 to 100% EtOAc in hexane, toafford(R)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide(77 mg, 49%) as a white solid. ¹H NMR (300 MHz, CDCl₃, 27° C.) 1.10-1.29(1H, m), 1.36-1.58 (3H, m), 1.84-2.04 (5H, m), 1.85-2.05 (5H, m),2.06-2.21 (4H, m), 2.25 (1H, br d), 2.41-2.55 (1H, m), 2.82-2.97 (4H,m), 3.76-3.99 (4H, m), 4.23 (2H, t), 5.66 (1H, d), 7.92 (1H, s), 8.13(1H, s), 8.21-8.33 (2H, m). m/z: ES+ [M+H]+ 472.

Optical Rotation:

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 20° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: DMSO

[α]=+79.7

Example 34:N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)-3-methyloxetane-3-carboxamide

HATU (140 mg, 0.37 mmol) was added to a solution of(1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamidedihydrochloride (150 mg, 0.34 mmol; prepared according to Example 31b),3-methyloxetane-3-carboxylic acid (43 mg, 0.37 mmol), DIPEA (0.18 mL,1.0 mmol) and DMF (1.2 mL). The reaction was stirred at r.t. for 3 h.The reaction was diluted with EtOAc and washed with saturated aqueoussodium hydrogencarbonate and saturated aqueous sodium chloride. Theorganic layer was dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The resulting residue was purified by flashsilica chromatography, eluting gradient 80 to 100% EtOAc in hexane, toaffordN-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)-3-methyloxetane-3-carboxamide(71 mg, 45%) as a white solid. 1H NMR (300 MHz, CDCl₃, 27° C.) 1.17-1.33(1H, m), 1.42-1.62 (6H, m), 1.86-2.16 (7H, m), 2.21-2.34 (1H, m),2.44-2.57 (1H, m), 2.90-2.99 (1H, m), 3.89-4.02 (1H, m), 4.24 (2H, t),4.46 (2H, d), 4.84-4.89 (2H, m), 5.86 (1H, d), 7.91 (1H, s), 8.09 (1H,br s), 8.19 (1H, s), 8.28 (1H, s). m/z: ES+ [M+H]+ 472.

Optical Rotation:

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 20° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: DMSO

[α]=+64.2

Example 35:(S)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide

HATU (140 mg, 0.37 mmol) was added to a solution of(1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamidedihydrochloride (150 mg, 0.34 mmol; prepared according to Example 31b),(S)-tetrahydrofuran-2-carboxylic acid (43 mg, 0.37 mmol), DIPEA (0.18mL, 1.0 mmol) and DMF (1.2 mL). The reaction was stirred at r.t. for 3h. The reaction was diluted with EtOAc and washed with saturated NaHCO₃and saturated aqueous sodium chloride. The organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresulting residue was purified by flash silica chromatography, elutiongradient 80 to 100% EtOAc in hexane, to afford(S)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide(41 mg, 26%) as a white solid. ¹H NMR (300 MHz, CDCl₃, 27° C.) 1.12-1.26(1H, m), 1.35-1.57 (3H, m), 1.79-2.15 (10H, m), 2.20-2.35 (2H, m),2.41-2.53 (1H, m), 2.94 (2H, t), 3.81-3.96 (3H, m), 4.23 (2H, t), 4.33(1H, dd), 6.60 (1H, d), 7.92 (1H, s), 8.26 (2H, s), 8.36 (1H, br s).m/z: ES+ [M+H]+ 472.

Optical Rotation:

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 20° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: DMSO

[α]=+54.1

Example 36:(R)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide

HATU (140 mg, 0.37 mmol) was added to a solution of(1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamidedihydrochloride (150 mg, 0.34 mmol; prepared according to Example 31b),(R)-tetrahydrofuran-2-carboxylic acid (43 mg, 0.37 mmol), DIPEA (0.18mL, 1.0 mmol) and DMF (1.2 mL). The reaction was stirred at r.t. for 3h. The reaction was diluted with EtOAc and washed with saturated aqueoussodium hydrogencarbonate and saturated aqueous sodium chloride. Theorganic layer was dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The resulting residue was purified by flashsilica chromatography, elution gradient 80 to 100% EtOAc in hexane, toafford(R)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide(55 mg, 35%) as a white solid. ¹H NMR (300 MHz, CDCl₃, 27° C.) 1.13-1.37(1H, m), 1.37-1.58 (3H, m), 1.82-2.17 (11H, m), 2.20-2.36 (2H, m), 2.51(1H, br s), 2.90-3.00 (1H, m), 3.81-3.98 (3H, m), 4.25 (2H, t), 4.33(1H, dd), 6.62 (1H, d), 7.96 (1H, s), 8.26 (1H, s), 8.27-8.31 (1H, s),8.78 (1H, br s). m/z: ES+ [M+H]+ 472.

Optical Rotation:

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 20° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: DMSO

[α]=+46.5

Example 37:(1S,3R)—N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-((S)-2-hydroxypropanamido)cyclohexanecarboxamide

HATU (140 mg, 0.37 mmol) was added to a solution of(1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamidedihydrochloride (150 mg, 0.34 mmol; prepared according to Example 31b),(S)-2-hydroxypropanoic acid (0.033 g, 0.37 mmol), DIPEA (0.18 mL, 1.0mmol) and DMF (1.2 mL). The reaction was stirred at r.t. for 3 h. Thereaction was diluted with EtOAc and washed with saturated aqueous sodiumhydrogencarbonate and saturated aqueous sodium chloride. The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. The resulting residue was purified by preparative HPLC(Waters XBridge Prep C18 column, 5μ silica, 19 mm diameter, 150 mmlength) using decreasingly polar mixtures of water (containing 0.2%ammonium hydroxide, pH 10) and MeCN as eluents. Fractions containingproduct were concentrated under reduced pressure to afford(1S,3R)—N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-((S)-2-hydroxypropanamido)cyclohexanecarboxamide(0.066 g, 44%) as a white solid. ¹H NMR (300 MHz, CDCl₃, 27° C.)1.15-1.31 (1H, m), 1.39-1.59 (6H, m), 1.87-2.17 (8H, m), 2.28 (1H, brd), 2.48-2.61 (1H, m), 2.96 (2H, t), 3.84-3.98 (1H, m), 4.20-4.28 (3H,m), 6.43 (1H, d), 7.95 (1H, s), 8.25 (1H, s), 8.33 (1H, s), 8.96 (1H, brs). m/z: ES+ [M+H]+ 446.

Optical Rotation:

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 20° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: DMSO

[α]=+56.6

Example 38:(S)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide

HATU (140 mg, 0.37 mmol) was added to a solution of(1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamidedihydrochloride (150 mg, 0.34 mmol; prepared according to Example 31b),(S)-tetrahydrofuran-3-carboxylic acid (43 mg, 0.37 mmol) DIPEA (0.18 mL,1.0 mmol) and DMF (1.2 mL). The reaction was stirred at r.t. for 3 h.The reaction was diluted with EtOAc and washed with saturated aqueoussodium hydrogencarbonate and saturated aqueous sodium chloride. Theorganic layer was dried over sodium sulfate, filtered and concentratedunder reduced pressure. The resulting residue was purified by flashsilica chromatography, elution gradient 80 to 100% EtOAc in hexane, toafford(S)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide(70 mg, 44%). ¹H NMR (300 MHz, CDCl₃, 27° C.) 1.09-1.26 (m, 1H),1.38-1.59 (m, 3H), 1.87-2.05 (m, 5H), 2.07-2.21 (m, 4H), 2.29 (1H, d),2.38-2.58 (1H, m), 2.82-2.99 (4H, m), 3.78-4.00 (4H, m), 4.24 (2H, t),5.63 (1H, d), 7.92 (1H, s), 8.25 (1H, s), 8.27 (1H, s), 8.40 (1H, br s).m/z: ES+ [M+H]+ 472.

Optical Rotation:

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 20° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: DMSO

[α]=+60.4

Example 39:(1S,3R)-3-acetamido-N-(5-cyano-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide

5,5-Dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(195 mg, 0.57 mmol; prepared according to Example 14),(1S,3R)-3-acetamido-N-(4-chloro-5-cyanopyridin-2-yl)cyclohexanecarboxamide(184 mg, 0.57 mmol), cesium carbonate (561 mg, 1.72 mmol), dioxane (4.3mL) and water (1.4 mL) were combined in a 100-mL round bottom flask togive a colorless solution. The solution was purged with nitrogen for 15min, and 2nd Generation X-Phos Precatalyst (33 mg, 0.04 mmol) was added.The reaction was heated at 95° C. under nitrogen for 1 hour, then cooledand diluted with DCM (50 mL). The organic layer was washed with water(2×25 mL) before being concentrated under reduced pressure. Theresulting residue was adsorbed onto silica gel and purified by flashcolumn chromatography, elution gradient 0 to 10% methanol in DCM.Product fractions were concentrated under reduced pressure, and theresulting residue was repurified by reverse phase HPLC (15 g RediSep RfGold(R) reversed-phase HP C18 column by Teledyne Isco, 10-40P silica),elution gradient 0 to 80% acetonitrile in water. Product fractions wereconcentrated under reduced pressure to afford(1S,3R)-3-acetamido-N-(5-cyano-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(59 mg, 24%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)0.99-1.19 (1H, m), 1.21-1.40 (9H. m), 1.73-1.84 (6H, m), 1.90 (1H, brs), 2.60-2.73 (1H, m), 2.95 (2H, s), 3.49-3.67 (1H, m), 3.97 (2H, s),7.74 (1H, d), 8.12 (1H, s), 8.31 (1H, s), 8.72 (1H, s), 10.90 (1H, s).m/z: ES+ [M+H]+ 421.

Procedures to prepare the starting material(1S,3R)-3-acetamido-N-(4-chloro-5-cyanopyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of 6-amino-4-chloronicotinonitrile

A degassed mixture of dicyanozinc (0.57 g, 4.8 mmol),5-bromo-4-chloropyridin-2-amine (1.00 g, 4.82 mmol),tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.24 mmol), and DMF(12 mL) was subjected to microwave conditions (170° C., 2 min). Thereaction was cooled and purified directly by flash silicachromatography, elution gradient 0 to 70% ethyl acetate in hexanes.Product fractions were combined and concentrated under reduced pressure.The resulting yellow oil was repurified using the same conditions justdescribed to afford 6-amino-4-chloronicotinonitrile (0.47 g, 64%) as anoff-white solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 6.63 (1H, s), 7.34(2H, br s), 8.38 (1H, s). ¹³C NMR (75 MHz, DMSO-d₆, 27° C.) 95.59 (1C,s) 107.12 (1C, s) 116.17 (1C, s) 143.41 (1C, s) 154.87 (1C, s) 162.32(1C, s). m/z: ES+ [M+H]+ 154.

Preparation of tert-butyl((1R,3S)-3-((4-chloro-5-cyanopyridin-2-yl)carbamoyl)cyclohexyl)carbamate

1-Chloro-N,N,2-trimethylprop-1-en-1-amine (0.23 mL, 1.7 mmol) was addedto a solution of(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (310mg, 1.27 mmol; prepared according to Example 2) in DCM (5.5 mL) at r.t.,resulting in a colorless solution. The reaction was maintained underthese conditions for 2 h, and this reaction was added directly to asolution of 6-amino-4-chloronicotinonitrile (178 mg, 1.16 mmol) andpyridine (0.37 ml, 4.6 mmol) in DCM (11 mL) at 0° C. The reaction wasallowed to warm to r.t. and was maintained under these conditions for 18h. The reaction was then diluted with DCM and washed with water andsaturated aqueous sodium chloride, dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The resulting residuewas adsorbed onto silica gel and purified flash silica chromatography,elution gradient 0 to 10% methanol in DCM. The resulting material wasrepurified by flash silica chromatography, elution gradient 0 to 100%ethyl acetate in hexanes, to afford tert-butyl((1R,3S)-3-((4-chloro-5-cyanopyridin-2-yl)carbamoyl)cyclohexyl)carbamate(330 mg, 75%) as a white solid. m/z: ES+ [M+Na⁺]+401.

Preparation of(1S,3R)-3-acetamido-N-(4-chloro-5-cyanopyridin-2-yl)cyclohexanecarboxamide

Hydrochloric acid in dioxane (4 M; 1.5 mL, 44 mmol) was added to asolution of tert-butyl((1R,3S)-3-((4-chloro-5-cyanopyridin-2-yl)carbamoyl)cyclohexyl)carbamate(330 mg, 0.87 mmol) in MeOH (2.9 mL) under nitrogen to give a colorlesssolution. After 2 h, the reaction was concentrated under reducedpressure to afford a white solid (302 mg). This solid was dissolved inDCM (4.8 mL) and triethylamine (0.61 mL, 4.4 mmol) and acetic anhydride(123 μL, 1.31 mmol) were added. The reaction was stirred at r.t. for 2 hand then diluted with DCM. The reaction mixture was washed with water(30 mL), and saturated aqueous sodium chloride (30 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresulting residue was adsorbed onto silica gel and purified by flashsilica chromatography, elution gradient 0 to 10% methanol in DCM thenisocratic 10% methanol in ethyl acetate, to afford(1S,3R)-3-acetamido-N-(4-chloro-5-cyanopyridin-2-yl)cyclohexanecarboxamide(184 mg, 66%) as a white solid. m/z: ES+ [M+H]+ 321.

Example 40:(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Mixture of Examples 41 and 42, Unknown Ratio

Acetic anhydride (0.20 mL, 2.2 mmol) was added to a stirred solution of(1S,3R)-3-amino-N-(5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(670 mg, 1.79 mmol), triethylamine (0.52 mL, 3.8 mmol) andN,N-dimethylpyridin-4-amine (11 mg, 0.09 mmol) in DCM (10 mL). Thereaction mixture was stirred at r.t. for 18 h. The mixture was purifiedby ion exchange chromatography using an SCX column, and the desiredproduct was eluted from the column using 1 M NH₃ in MeOH. Productfractions were concentrated under reduced pressure. The resulting crudeproduct was purified by flash silica chromatography, using an elutiongradient of 0 to 100% EtOAc in heptane followed by isocratic 10% MeOH inEtOAc. Pure fractions were concentrated under reduced pressure to afford(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(693 mg, 93%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.)1.05-1.11 (1H, m), 1.23 (3H, d), 1.27-1.38 (3H, m), 1.72-1.81 (6H, m),1.89 (1H, br d), 2.52-2.63 (1H, m), 2.67 (1H, dd), 3.13-3.19 (1H, m),3.20-3.28 (1H, m), 3.50-3.63 (1H, m), 3.76 (1H, dd), 4.27-4.37 (1H, m),7.75 (1H, d), 8.00 (1H, s), 8.27 (1H, s), 8.35 (1H, s), 10.55 (1H, s).m/z: ES+ [M+H]+ 416.

Procedures used to prepare the starting material(1S,3R)-3-amino-N-(5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of 5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-one

n-Butyl lithium in hexane (1.6 M; 49.9 mL, 79.8 mmol) was added dropwiseto 2-methyl-3-(1H-pyrazol-1-yl)propanoic acid (4.92 g, 31.9 mmol) in THF(150 mL) at −78° C. over a period of 20 minutes under nitrogen. Theresulting suspension was stirred at −78° C. for 15 minutes. The reactionmixture was then warmed to −45° C. and maintained under these conditionsfor 30 mins before being allowed to warm to 15° C. The reaction was thenpoured slowly into ice cold saturated aqueous NH₄Cl (100 mL). Themixture was diluted with Et₂O (100 mL), the phases separated, and theaqueous layer was extracted with Et₂O (50 mL). The combined organiclayers were washed with saturated aqueous sodium chloride (50 mL), driedwith MgSO₄, filtered, and concentrated under reduced pressure. Theresulting oil was purified by flash silica chromatography, elutiongradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated todryness to afford 5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-one(1.3 g, 30%) as a colourless oil. ¹H NMR (400 MHz, CDCl₃, 21° C.) 1.45(3H, d), 3.27-3.38 (1H, m), 4.09 (1H, dd), 4.74 (1H, dd), 6.65 (1H, d),7.79 (1H, d).

Preparation of 5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

Hydrazine hydrate (2.28 mL, 47.0 mmol) was added to a stirred solutionof 5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-one (1.28 g, 9.40mmol) in diethylene glycol (26.8 mL, 282 mmol). The resulting solutionwas stirred at 180° C. for 1 hour. The reaction mixture was then allowedto cool slightly. Potassium hydroxide (1.85 g, 32.9 mmol) was carefullyadded to the mixture, and the resulting suspension was stirred at 150°C. for 2 h. The mixture was then allowed to cool before being dilutedwith water, acidified with dilute 2 M HCl to pH 4.5, and extracted withEt₂O (5×30 mL). The combined organic layers were washed with water (3×20mL) and saturated aqueous sodium chloride (20 mL), dried over MgSO₄,filtered, and concentrated under reduced pressure to give5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (0.98 g, 86%) as a clearcolorless oil. ¹H NMR (500 MHz, CDCl₃, 30° C.) 1.28 (3H, d), 2.39-2.54(1H, m), 2.99-3.16 (2H, m), 3.66-3.76 (1H, m), 4.23-4.33 (1H, m), 5.92(1H, d), 7.48 (1H, d).

Preparation of 3-iodo-5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

NIS (1.81 g, 8.04 mmol) was added portionwise to5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (0.89 g, 7.31 mmol) inacetonitrile (15 mL) at r.t. under nitrogen. The reaction mixture wasstirred at 23° C. for 18 h. The reaction mixture was diluted with EtOAc(20 mL) and washed sequentially with water (20 mL) and saturated aqueoussodium chloride (10 mL). The organic layer was dried over MgSO₄,filtered and concentrated under reduced pressure to afford3-iodo-5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (1.8 g, 99%) as anorange oil. ¹H NMR (500 MHz, CDCl₃, 30° C.) 1.28 (3H, d), 2.43 (1H, dd),3.00 (1H, dd), 3.06-3.14 (1H, m), 3.79 (1H, dd), 4.36 (1H, dd), 7.46(1H, s). m/z: ES+ [M+H]+ 249.

Preparation of5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

Isopropylmagnesium chloride lithium chloride complex in THF (1.3 M; 6.85mL, 8.91 mmol) was added dropwise to3-iodo-5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (1.7 g, 6.9 mmol)in THF (20 mL) at 0° C. over a period of 5 minutes under nitrogen. Theresulting mixture was stirred at 0° C. for 30 minutes.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.10 mL, 10.3mmol) was then added dropwise to the mixture keeping the internaltemperature at 0° C. The reaction mixture was then allowed to warm tor.t. overnight before being diluted with EtOAc (50 mL) and washedsequentially with saturated aqueous NH₄Cl (50 mL), water (50 mL), andsaturated aqueous sodium chloride (50 mL). The organic layer was driedover MgSO₄, filtered and evaporated to afford5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(1.5 g, 87%) as a pale brown oil that crystallised. ¹H NMR (400 MHz,CDCl₃, 22° C.) 1.26 (3H, d), 1.29 (12H, s), 2.57 (1H, dd), 3.01-3.22(2H, m), 3.64-3.75 (1H, m), 4.27 (1H, ddd), 7.76 (1H, s).

Preparation of tert-butyl((1R,3S)-3-((5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate

2nd Generation XPhos Precatalyst (0.25 g, 0.31 mmol) was added to adegassed mixture of5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(1.03 g, 3.75 mmol), tert-butyl((1R,3S)-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate(1.5 g, 3.13 mmol; prepared according to Example 10) and dibasicpotassium phosphate (1.63 g, 9.38 mmol) in 1,4-dioxane (15 mL) and water(3 mL). The resulting mixture was degassed and stirred at 90° C. for 18h under nitrogen. The reaction mixture was then allowed to cool to r.t.,diluted with EtOAc (100 mL) and washed sequentially with water (100 mL)and saturated aqueous sodium chloride (50 mL). The organic extract wasdried over MgSO₄, filtered, and concentrated under reduced pressure. Theresulting residue was purified by flash silica chromatography, elutiongradient 0 to 70% EtOAc in heptane. Pure fractions were concentratedunder reduced pressure to afford tert-butyl((1R,3S)-3-((5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(1.0 g, 69%) as a yellow foam. ¹H NMR (400 MHz, DMSO, 30° C.) 1.07-1.12(1H, m), 1.70-1.82 (3H, m), 1.85-1.93 (1H, m), 2.53-2.62 (1H, m), 2.66(1H, dd), 3.11-3.18 (1H, m), 3.19-3.29 (1H, m), 3.76 (1H, dd), 4.32 (1H,dd), 6.76 (1H, d), 8.00 (1H, s), 8.27 (1H, s), 8.34 (1H, s), 10.52 (1H,s). m/z: ES+ [M+H]+ 474.

Preparation of(1S,3R)-3-amino-N-(5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Tert-butyl((1R,3S)-3-((5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(1.11 g, 2.34 mmol) was dissolved in DCM (20 mL). Trifluoroacetic acid(1.8 mL, 23 mmol) was added and the reaction mixture was stirred at r.t.for 18 h. The reaction was purified by ion exchange chromatography usingan SCX column. The desired product was eluted from the column using 1 MNH₃ in MeOH, and pure fractions were evaporated to dryness to afford(1S,3R)-3-amino-N-(5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.68 g, 77%) as a white solid. m/z: ES+ [M+H]+ 374.

Examples 41 and 42: Isomer 1 and isomer 2 of(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Pure Enantiomers

The configuration of the methyl is unknown for Example 41 and 42, but isopposite in Example 41 vs. Example 42

(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(670 mg, 1.79 mmol; Example 40) was resolved by preparative HPLC (ChiralTechnologies IA column, 20 μm silica, 100 mm diameter, 250 mm length),using a 70/15/15 mixture of heptane/EtOH/MeOH as eluents and a flow rateof 450 mL/min, fractions containing the desired compounds wereconcentrated under reduced pressure to give the faster eluting isomer 1of(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(356 mg, 48%) and the slower eluting isomer 2 of(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(348 mg, 47%).

Example 41: Isomer 1 of(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide

¹H NMR (400 MHz, DMSO-d₆, 30° C.) 1.05-1.15 (1H, m), 1.25 (3H, d),1.26-1.39 (3H, m), 1.72-1.83 (6H, m), 1.90 (1H, br d), 2.55-2.62 (1H,m), 2.67 (1H, dd), 3.11-3.19 (1H, m), 3.21-3.28 (1H, m), 3.51-3.62 (1H,m), 3.76 (1H, dd), 4.27-4.37 (1H, m), 7.75 (1H, d br), 8.00 (1H, s),8.27 (1H, s), 8.35 (1H, s), 10.55 (1H, s). m/z: ES+ [M+H]+ 416.

Example 42: Isomer 2 of(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide

¹H NMR (400 MHz, DMSO-d₆, 30° C.) 1.08-1.13 (1H, m), 1.24 (3H, d),1.25-1.36 (3H, m), 1.62-1.85 (6H, m), 1.91 (1H, br d), 2.52-2.61 (1H,m), 2.67 (1H, dd), 3.13-3.19 (1H, m), 3.21-3.29 (1H, m), 3.51-3.60 (1H,m), 3.76 (1H, dd), 4.32 (1H, dd), 7.74 (1H, d), 7.98 (1H, s), 8.28 (1H,s), 8.34 (1H, s), 10.54 (1H, s).

Analytical Reverse Phase Chiral Conditions:

Column: Chiral Technologies IA column,

Column Dimensions: 5 m, 4.6 mm diameter, 250 mm length,

Mobile Phase A: Heptane

Mobile Phase B: 1:1 EtOH:MeOH

Gradient: Isocratic 30% Mobile Phase B

Flow Rate: 2 mL/min over 15 min

Retention Time: 7.9 min, Isomer 1

-   -   9.3 min, Isomer 2        e.e. 99.4%, Isomer 1    -   97.6%, Isomer 2

Example 43:(1R,3S)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamideand(1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(Example 14)

2nd Generation XPhos Precatalyst (0.019 g, 0.02 mmol) and cesiumcarbonate (0.464 g, 1.42 mmol) were added to a degassed solution of5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(1.6 mL, 0.50 mmol, as a 0.106 g/mL solution in dioxane; preparedaccording to Example 14),cis-3-acetamido-N-(5-chloro-4-iodopyridin-2-yl)cyclohexanecarboxamide(0.20 g, 0.47 mmol; prepared according to Examples 10 and 12,substituting cis-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylicacid (prepared in Example 2, Intermediates) for(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid andacetyl chloride for acetic anhydride), 1,4-dioxane (2.6 mL), and water(0.52 mL). The resulting mixture was immersed in a preheated oil bathset at 85° C. After 3 h, another 300 μL of5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolestock solution (0.106 g/mL in dioxane) were added to the now lightorange reaction. The reaction was maintained at this temperature foranother 45 min and then cooled to r.t. The reaction was diluted withsaturated aqueous sodium chloride and extracted with ethyl acetate (×2).The combined organic layers were dried over sodium sulfate, filtered,and concentrated under reduced pressure. The resulting yellow residuewas purified by flash silica chromatography, elution gradient 10 to 100%ethyl acetate in hexanes then 0 to 20% methanol in ethyl acetate, toaffordcis-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.147 g, 72%) contaminated with a small amount of pinacol diol as anoff-white solid.

This material was resolved into its enantiomers using SFC conditions(Column: (S,S) Whelk-O1, 5 μm, 21.2 mm diameter, 250 mm length, 40° C.column temperature, 100 bar outlet pressure, 75 mL/min flow rate),eluting with 30% isopropanol in CO₂, to afford Example 14,(1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.053 g, 26%), as a white foam solid and Example 43,(1R,3S)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.061 g, 30%), as a white foam solid.

(1R,3S)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(Example 43)

¹H NMR (300 MHz, DMSO-d₆, 27° C.) 1.05 (1H, d), 1.22-1.40 (9H, m), 1.78(6H, s), 1.90 (1H, d), 2.56-2.69 (1H, m), 2.89 (2H, s), 3.47-3.65 (1H,m), 3.95 (2H, s), 7.74 (1H, br d), 7.99 (1H, s), 8.25 (1H, s), 8.35 (1H,s), 10.54 (1H, s). m/z: ES+ [M+H]+ 430.

Analytical SFC Conditions:

Column: (S,S) Whelk-Ol1

Column Dimensions: 5 μm, 4.6 mm diameter, 100 mm length,

Column Temperature: 40° C.

Mobile Phase A: CO₂ (100%)

Mobile Phase B: Isopropanol

Gradient: Isocratic 30% Mobile Phase B

Flow Rate: 5 mL/min over 5 min

Retention Time: 2.92 min, Example 14

-   -   3.54 min, Example 43        e.e. >98%, Example 14    -   95.5%, Example 43

Optical Rotation for(1R,3S)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(Example 43)

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 20° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: DMSO

[α]=−60.6

Example 44:(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Acetic anhydride (0.022 mL, 0.23 mmol) was added to a stirred solutionof(1S,3R)-3-amino-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(70 mg, 0.19 mmol), triethylamine (0.056 mL, 0.40 mmol), andN,N-dimethylpyridin-4-amine (1.2 mg, 9.5 μmol) in DCM (10 mL). Thereaction mixture was stirred at r.t. for 4 h, and the crude reaction waspurified by ion exchange chromatography using an SCX column. The desiredproduct was eluted from the column using 1 M NH₃ in MeOH andproduct-containing fractions were concentrated under reduced pressure.The resulting residue was further purified by preparative HPLC (WatersXBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length),using decreasingly polar mixtures of water (containing 1% NH₃) and MeCNas eluents. Fractions containing the desired compound were concentratedunder reduced pressure to afford(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(44 mg, 56%) as a solid. ¹H NMR (500 MHz, DMSO-d₆, 30° C.) 1.04 (6H, s),1.06-1.15 (1H, m), 1.32-1.38 (3H, m), 1.66-1.82 (6H, m), 1.83-1.94 (3H,m), 2.58-2.64 (1H, m), 2.78 (2H, s), 3.54-3.62 (1H, m), 4.14 (2H, t),7.16 (1H, dd), 7.76 (1H, d), 7.84 (1H, s), 8.18 (1H, s), 8.24 (1H, d),10.34 (1H, s). m/z: ES+ [M+H]+ 410.

Procedures for preparing the starting material(1S,3R)-3-amino-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of ethyl 1-(4-ethoxy-4-oxobutyl)-1H-pyrazole-5-carboxylate

Ethyl 4-bromobutanoate (10 mL, 71 mmol) was added to a stirred mixtureof ethyl 1H-pyrazole-5-carboxylate (9.9 g, 71 mmol) and potassiumcarbonate (11.7 g, 84.8 mmol) in DMF (70 mL). The mixture was stirred atr.t. for 24 h. Water was added and the mixture was extracted with ethylacetate (3×). The combined organic layers were washed with water (2×),dried over MgSO₄, and concentrated under reduced pressure. The resultingresidue was purified by flash silica chromatography, eluting with 20%ethyl acetate in pentane to afford desired ethyl1-(4-ethoxy-4-oxobutyl)-1H-pyrazole-5-carboxylate (9.0 g, 50%) as asolid. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.24 (3H, t), 1.38 (3H, t),2.11-2.25 (2H, m), 2.25-2.38 (2H, m), 4.12 (2H, q), 4.34 (2H, q), 4.63(2H, t), 6.83 (1H, d), 7.47 (1H, d). m/z: ES+ [M+H]+ 255. Also isolatedwas ethyl 1-(4-ethoxy-4-oxobutyl)-1H-pyrazole-3-carboxylate (8 g,44.5%).

Preparation of ethyl4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylate

Potassium tert-butoxide (1.39 g, 12.4 mmol) was added to a stirringsolution of ethyl 1-(4-ethoxy-4-oxobutyl)-1H-pyrazole-5-carboxylate (2.1g, 8.3 mmol) in toluene (20 mL). The mixture was stirred at r.t. for 10minutes and was then warmed to 110° C., resulting in formation of athick precipitate. The mixture was heated under these conditions for 30minutes and then cooled to r.t. before being acidified with dilute HCland extracted with ethyl acetate (3×). The combined organic layers weredried over MgSO₄, filtered, and concentrated under reduced pressure toafford ethyl4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylate (1.7 g,99%) as a solid. m/z: ES+ [M+H]+ 209.

Preparation of 6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one

Lithium chloride (0.458 g, 10.8 mmol) was added to a stirred solution ofethyl 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-5-carboxylate (1.5g, 7.2 mmol) in DMSO (15 mL). The mixture was heated at 120° C. for 24 hthen cooled to r.t. Water was added, and the mixture was extracted withethyl acetate (3×). The combined organic layers were combined andconcentrated under reduced pressure. The resulting residue was purifiedby flash silica chromatography, eluting with 50% ethyl acetate inheptane to give 6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (0.90 g,92%) as a solid. ¹H NMR (400 MHz, CDCl₃, 30° C.) 2.26-2.45 (2H, m),2.65-2.75 (2H, m), 4.35-4.45 (2H, m), 6.87 (1H, d), 7.55 (1H, d).

Preparation of 5,5-dimethyl-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one

Sodium hydride (60 wt % in mineral oil; 705 mg, 17.6 mmol) was added toa solution of 6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (800 mg, 5.88mmol) in DMF (5.0 mL) at 0° C. The mixture was stirred for 10 minutesunder these conditions and then iodomethane (1.10 mL, 17.6 mmol) wasadded. The ice bath was removed, and the reaction was maintained underthese conditions for 18 h. Water was added, and the mixture wasacidified with dilute aqueous hydrochloric acid to pH 7. The reactionwas then extracted with ether (3×), and the combined organic layers weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The resulting residue was purified by flash silicachromatography, eluting with 30% ethyl acetate in heptane to afford5,5-dimethyl-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (800 mg, 83%)as a white solid. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.27 (6H, s),2.06-2.26 (2H, m), 4.32-4.5 (2H, m), 6.86 (1H, d), 7.54 (1H, d). m/z:ES+ [M+H]+ 165.

Preparation of 5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine

Hydrazine hydrate (1.18 mL, 24.4 mmol) was added to a stirred solutionof 5,5-dimethyl-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (800 mg,4.87 mmol) dissolved in diethylene glycol (10 mL, 105 mmol). Theresulting solution was stirred at 180° C. for 1 hour. The reaction wasthen removed from heat, and potassium hydroxide (957 mg, 17.1 mmol) wascarefully added to the mixture. The resulting suspension was stirred at170° C. for 2 h. After cooling, the reaction mixture was diluted withwater, acidified to pH 5 with dilute aqueous hydrochloric acid (2N), andextracted with Et₂O (5×50 mL). The combined organic layers were washedwith water (2×20 mL) and then dried over MgSO₄, filtered, andconcentrated under reduced pressure to give5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (650 mg, 89%) asa solid. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.05 (6H, s), 1.66-1.97 (2H,m), 2.57 (2H, s), 4.15 (2H, t), 5.92-5.94 (1H, m), 7.44 (1H, d).

Preparation of3-iodo-5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine

NIS (1.07 g mg, 4.76 mmol) was added to a stirred solution of5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (650 mg, 4.33mmol) dissolved in acetonitrile (10 mL) at 23° C. The resulting mixturewas stirred at 23° C. for 16 h. The reaction mixture was then dilutedwith EtOAc (20 mL) and washed sequentially with water (2×20 mL) andsaturated aqueous sodium chloride (20 mL). The organic layer was driedover MgSO₄, filtered, and concentrated under reduced pressure to affordcrude 3-iodo-5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (1.1g, 92%) as a solid. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.07 (6H, s), 1.80(2H, t), 2.43 (2H, s), 4.24 (2H, t), 7.48 (1H, s).

Preparation of tert-butyl((1R,3S)-3-((4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate

Dichloro[1,1′-bis(di-t-butylphosphino)ferrocene]palladium(II) (44 mg,0.070 mmol) was added to a degassed solution of tert-butyl((1R,3S)-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(300 mg, 0.67 mmol; prepared according to Example 16),3-iodo-5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (242 mg,0.88 mmol), and potassium phosphate, tribasic (429 mg, 2.02 mmol), in1,4-dioxane (10 mL) and water (1 mL). The resulting mixture was stirredat 90° C. for 18 h. The crude reaction was cooled and purified by ionexchange chromatography using an SCX column. The desired product waseluted from the column using 1 M NH₃ in MeOH, and product-containingfractions were concentrated under reduced pressure to afford crudeproduct as a brown oil. The crude product was purified by flash silicachromatography, elution gradient 0 to 100% EtOAc in heptane. Purefractions were concentrated under reduced pressure to afford tert-butyl((1R,3S)-3-((4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(170 mg, 54%) as a solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.) 1.03 (6H,s), 1.04-1.15 (1H, m), 1.21-1.41 (12H, m), 1.72-1.81 (3H, m), 1.83-1.92(3H, m), 2.53-2.62 (1H, m), 2.65-2.69 (2H, m), 4.16 (2H, t), 6.76 (1H,br d), 7.76 (1H, d), 8.19 (1H, d), 8.29 (1H, d), 10.43 (1H, s). Broad(1H) multiplet underneath base of HOD peak at 3.3 ppm. m/z: ES+ [M+H]+468.

Preparation of(1S,3R)-3-amino-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Trifluoroacetic acid (1 mL) was added to tert-butyl((1R,3S)-3-((4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(170 mg, 0.36 mmol) in DCM (10 mL). The resulting mixture was stirred atr.t. for 6 h. The reaction was then concentrated under reduced pressure,and the resulting residue was subjected to ion exchange chromatographyusing an SCX column. The desired product was eluted from the columnusing 2 M NH₃ in MeOH. Product fractions were concentrated under reducedpressure, and the resulting residue was purified by flash silicachromatography, eluting with 7% (1% ammonia in methanol) in DCM toafford(1S,3R)-3-amino-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(70 mg, 52%) as a solid. m/z: ES+ [M+H]+ 368.

Example 45:(S)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide

HATU (118 mg, 0.31 mmol) was added to a solution of(S)-tetrahydrofuran-2-carboxylic acid (0.03 mL, 0.31 mmol),(1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(100 mg, 0.26 mmol; prepared according to Example 14) and triethylamine(0.11 mL, 0.77 mmol) in DMA (2 mL). The reaction mixture was stirred atr.t. for 16 h and then quenched with water (20 mL). The mixture wasextracted with DCM (50 mL), and the organic layer was washed with brine(50 mL). The organic layer was dried over MgSO₄, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30mm diameter, 100 mm length) using decreasingly polar mixtures of water(containing 1% NH₃) and MeCN as eluents. Fractions containing thedesired compound were concentrated under pressure to afford(S)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide(59 mg, 47%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆, 30° C.)1.19-1.36 (9H, s), 1.49 (1H, q), 1.70 (1H, d), 1.74-1.89 (6H, m),2.02-2.16 (1H, m), 2.58-2.68 (1H, m), 2.90 (2H, s), 3.63 (1H, dd), 3.75(1H, q), 3.89 (1H, q), 3.95 (2H, s), 4.17 (1H, dd), 7.60 (1H, d), 8.00(1H, s), 8.26 (1H, s), 8.31-8.38 (1H, m), 10.55 (1H, s). m/z: ES+ [M+H]+486.

Example 46:(R)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide

HATU (118 mg, 0.31 mmol) was added to a solution of(R)-tetrahydrofuran-2-carboxylic acid (0.03 mL, 0.31 mmol),(1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(100 mg, 0.26 mmol; prepared according to Example 14) and triethylamine(0.11 mL, 0.77 mmol) in DMA (2 mL). The reaction mixture was stirred atr.t. for 16 h and then quenched with water (20 mL). The mixture wasextracted with DCM (50 mL), and the organic layer was washed withsaturated aqueous sodium chloride (50 mL), dried over MgSO₄, filtered,and concentrated under reduced pressure. The resulting residue waspurified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5silica, 30 mm diameter, 100 mm length) using decreasingly polar mixturesof water (containing 1% NH₃) and MeCN as eluents. Fractions containingthe desired compound were evaporated to dryness to afford(R)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide(61 mg, 49%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆, 30° C.)1.20-1.37 (9H, s), 1.49 (1H, q), 1.70 (1H, d), 1.75-1.9 (6H, m),2.04-2.16 (1H, m), 2.58-2.68 (1H, m), 2.90 (2H, s), 3.58-3.67 (1H, m),3.75 (1H, q), 3.89 (1H, q), 3.95 (2H, s), 4.17 (1H, dd), 7.60 (1H, d),8.00 (1H, s), 8.26 (1H, s), 8.35 (1H, s), 10.55 (1H, s). m/z: ES+ [M+H]+486.

Example 47:(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-methylpyridin-2-yl)cyclohexanecarboxamide

5,5-Dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(94 mg, 0.26 mmol; prepared according to Example 23) was added to asolution of(1S,3R)-3-acetamido-N-(4-iodo-5-methylpyridin-2-yl)cyclohexanecarboxamide(100 mg, 0.25 mmol) in 1,4-dioxane (2.1 mL) and water (0.4 mL) to give acolorless solution. The solution was purged with nitrogen for 10 min,and then cesium carbonate (244 mg, 0.75 mmol) and 2nd Generation XPhosPrecatalyst (19.6 mg, 0.02 mmol) were added. The reaction was heated at85° C. for 7 hr and then cooled to r.t. The reaction was diluted withEtAOc (50 mL) and then washed with water and saturated aqueous sodiumchloride. The organic layer was concentrated under reduced pressure, andthe resulting residue was adsorbed onto silica gel and purified by flashsilica chromatography, eluting with 0 to 10% MeOH in DCM, to afford(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-methylpyridin-2-yl)cyclohexanecarboxamide(37 mg, 36%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.00-1.16 (1H, m), 1.27 (9H, s), 1.78 (6H, s), 1.85-1.96 (1H, m), 2.33(3H, s), 2.55-2.65 (1H, m), 2.86 (2H, s), 3.88-3.97 (2H, m), 7.75 (1H,d), 7.82 (1H, s), 7.98 (1H, s), 8.13 (1H, s), 10.45 (1H, br s). m/z: ES+[M+H]+ 410.

Optical Rotation:

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 25° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: DMSO

[α]=+39.7

Procedures used to prepare the starting material(1S,3R)-3-acetamido-N-(4-iodo-5-methylpyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of 4-iodo-5-methylpyridin-2-amine

A white suspension of 2-fluoro-4-iodo-5-methylpyridine (3.00 g, 12.7mmol) and concentrated aqueous ammonium hydroxide (3.5 mL, 90 mmol) inDMSO (17 mL) was subjected to microwave conditions (140° C., 4 h) andthen cooled. The reaction was diluted with EtOAc and water, and thelayers were separated. The aqueous layer was extracted with EtOAc (3×50mL), and the combined organic layers were concentrated under reducedpressure. The resulting residue was adsorbed onto silica gel andpurified by flash silica chromatography, elution gradient 0 to 10% MeOHin DCM, to afford 4-iodo-5-methylpyridin-2-amine (800 mg, 27%) as awhite solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 2.13 (s, 3H) 5.81 (s, 2H)6.99 (s, 1H) 7.75 (s, 1H). m/z: ES+ [M+H]+ 235.

Preparation of tert-butyl((1R,3S)-3-((4-iodo-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)carbamate

1-Chloro-N,N,2-trimethylprop-1-en-1-amine (0.24 mL, 1.8 mmol) was addedto a solution of(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (321mg, 1.32 mmol; prepared according to Example 2) in DCM (2.8 mL) to givea colorless solution. The solution was stirred at r.t. for 2 h and thenadded a solution of 4-iodo-5-methylpyridin-2-amine (281 mg, 1.2 mmol)and pyridine (0.24 mL, 3.0 mmol) in DCM (2.8 mL) at 0° C. The reactionwas allowed to warm to r.t. and stirred under these conditions 3 hbefore being diluted with DCM and washed with saturated aqueous NaHCO₃,water, and saturated aqueous sodium chloride. The organic layer wasdried over sodium sulfate, filtered, and concentrated under reducedpressure. The resulting residue was adsorbed onto silica gel andpurified by flash silica chromatography, elution gradient 0 to 10% MeOHin DCM, to afford tert-butyl((1R,3S)-3-((4-iodo-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)carbamate(530 mg, 96%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.02-1.13 (1H, m), 1.44-1.53 (3H, m), 1.38 (9H, s), 1.65-1.80 (3H, m),1.87 (1H, br d), 2.29 (3H, s), 2.52-2.61 (1H, m), 3.19-3.34 (1H, m),6.78 (1H, br d), 8.16 (1H, s), 8.61 (1H, s), 10.43 (1H, s). m/z: ES+[M+H]+ 460.

Preparation of(1S,3R)-3-acetamido-N-(4-iodo-5-methylpyridin-2-yl)cyclohexanecarboxamide

Hydrochloric acid dioxane (4 M; 2.1 mL, 8.6 mmol) was added totert-butyl((1R,3S)-3-((4-iodo-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)carbamate(393 mg, 0.86 mmol) in MeOH (4.3 mL) to give a colorless solution. Thereaction was stirred at r.t. for 4 h, resulting in a white mixture. Thereaction was concentrated under reduced pressure to afford a whitesolid. TEA (0.60 mL, 4.3 mmol) and acetic anhydride (0.16 mL, 1.7 mmol)were added, and the reaction was stirred at r.t. for 1 hour. The mixturewas then diluted with DCM, and washed with water and saturated aqueoussodium chloride. The organic layer was concentrated under reducedpressure, and the resulting residue was adsorbed onto silica gel andpurified by flash silica chromatography, elution gradient 0 to 10% MeOHin DCM to afford(1S,3R)-3-acetamido-N-(4-iodo-5-methylpyridin-2-yl)cyclohexanecarboxamide(100 mg, 29%) as a clear oil. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.04-1.13 (1H, m), 1.19-1.39 (3H, m), 1.69-1.81 (6H, m), 1.86 (1H, brd), 2.29 (3H, s), 2.55-2.61 (1H, m), 3.41-3.62 (1H, m), 7.75 (1H, br d),8.16 (1H, s), 8.61 (1H, s), 10.45 (1H, s). m/z: ES+ [M+H]+ 402.

Example 48:(1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclopentanecarboxamide

Acetic anhydride (0.25 mL, 2.67 mmol) was added to(1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclopentanecarboxamide(500 mg, 1.34 mmol) and TEA (0.64 mL, 4.6 mmol) in DCM (10 mL) and MeOH(2 mL) under nitrogen. The resulting suspension was stirred at r.t. for6 h. The reaction mixture was then diluted with DCM and washedsequentially with saturated aqueous ammonium chloride and water beforebeing dried over magnesium sulfate, filtered, and concentrated underreduced pressure. The resulting residue was purified by preparative HPLC(Waters SunFire column, 5μ silica, 30 mm diameter, 100 mm length), usingdecreasingly polar mixtures of water (containing 0.1% formic acid) andMeCN as eluents. Fractions containing the desired compound wereconcentrated under reduced pressure to afford(1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclopentanecarboxamide(340 mg, 61%) as a solid. ¹H NMR (500 MHz, DMSO, 30° C.) 1.28 (6H, s),1.45-1.51 (1H, m), 1.62 (1H, dt), 1.79 (3H, s), 1.81-1.89 (3H, m), 2.15(1H, dt), 2.90 (2H, s), 3.00 (1H, dq), 3.95 (2H, s), 4.04 (1H, dq), 7.90(1H, d), 8.00 (1H, s), 8.28 (1H, s), 8.35 (1H, s), 10.58 (1H, s). m/z:ES+ [M+H]+ 416.

Procedures used to prepare the starting material(1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclopentanecarboxamideare described below:

Preparation of tert-butyl((1R,3S)-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclopentyl)carbamate

T₃P (≥50 wt % in ethyl acetate; 2.60 mL, 4.36 mmol) was added to asolution of 5-chloro-4-iodopyridin-2-amine (694 mg, 2.18 mmol; preparedaccording to Example 2),(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclopentanecarboxylic acid (500mg, 2.18 mmol) and pyridine (0.71 mL, 8.7 mmol) in EtOAc (10 mL). Theresulting solution was stirred at r.t. for 24 h. The reaction mixturewas diluted with saturated aqueous ammonium chloride (25 mL) andextracted with EtOAc (50 mL). The organic layer was dried over MgSO₄,filtered, and concentrated under reduced pressure to afford tert-butyl((1R,3S)-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclopentyl)carbamate(650 mg, 64%). ¹H NMR (400 MHz, DMSO-d₆, 30° C.) 1.39 (9H, s), 1.46-1.63(2H, m), 1.74-183 (3H, m), 2.04-2.17 (1H, m), 2.90-3.00 (1H, m),3.70-3.84 (1H, m), 6.73-6.82 (1H, m), 8.39 (1H, s), 8.73 (1H, s), 10.68(1H, s). m/z: ES+ [M+H]+ 466.

Preparation of tert-butyl((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclopentyl)carbamate

5,5-Dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(665 mg, 1.95 mmol; prepared according to Example 23) was added totert-butyl((1R,3S)-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclopentyl)carbamate(650 mg, 1.40 mmol), 2nd Generation XPhos Precatalyst (110 mg, 0.14mmol) and potassium phosphate, dibasic (729 mg, 4.19 mmol) in1,4-dioxane (20 mL) and water (4 mL) under nitrogen. The resultingsuspension was stirred at 85° C. for 20 h. The reaction mixture wasdiluted with EtOAc (50 mL), and washed sequentially with water (2×25 mL)and saturated aqueous sodium chloride (25 mL). The organic layer wasdried over MgSO₄, filtered, and concentrated under reduced pressure. Theresulting residue was purified by flash silica chromatography, elutingwith 25 to 70% EtOAc in heptane. Pure fractions were evaporated todryness to afford tert-butyl((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclopentyl)carbamate(600 mg, 91%) as a white solid. m/z: ES+ [M+H]+ 474.

Preparation of(1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclopentanecarboxamide

Hydrochloric acid in dioxane (4 M; 1.6 mL, 6.3 mmol) was added slowly totert-butyl((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclopentyl)carbamate(600 mg, 1.27 mmol) in DCM (10 mL) under nitrogen. The resultingsuspension was stirred at r.t. for 4 h and then stored in the fridge fora 72 hour period. The reaction mixture was then diluted with DCM (10 mL)and MeOH (2 mL), and hydrochloric acid in dioxane (4 M; 1.6 mL, 6.3mmol) was added under nitrogen. The resulting suspension was stirred atr.t. for an additional 18 h and then concentrated under reducedpressure. The resulting residue was purified by ion exchangechromatography using an SCX column. The desired product was eluted fromthe column using 1 M NH₃ in MeOH, and product fractions wereconcentrated under reduced pressure to afford(1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclopentanecarboxamide(473 mg, 99%) as a yellow oil. ¹H NMR (500 MHz, DMSO-d₆, 27° C.) 1.28(6H, s), 1.49 (1H, dd), 1.59 (1H, dd), 1.73 (1H, dd), 1.91 (2H, q), 2.04(1H, td), 2.89-2.93 (3H, m), 3.78-3.83 (1H, m), 3.95 (2H, s), 8.00 (1H,s), 8.27 (1H, s), 8.34 (1H, s). Amide NH not observed; NH₂ signalassumed to be under broad water peak. m/z: ES+ [M+H]+ 374.

Example 49:(1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Methoxy(cyclooctadiene)iridium(I) dimer (54 mg, 0.08 mmol) was added to4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine (100 mg, 0.81 mmol),4,4,5,5-tetramethyl-1,3,2-dioxaborolane (312 mg, 2.44 mmol), and4,4′-di-tert-butyl-2,2′-dipyridyl (44 mg, 0.16 mmol) in THF (2 mL) undernitrogen. The resulting mixture was stirred at 90° C. for 3 h. Uponcooling, approximately 2.3 mL of reaction mixture containing crude3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridinewas obtained as a suspension. m/z: ES+ [M+3H—(C(CH₃)₂)₂]+ 168.

Crude3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine(approximately 0.3 mL of the reaction suspension above) was added to amixture of(1S,3R)-3-acetamido-N-(5-chloro-4-iodopyridin-2-yl)cyclohexanecarboxamide(10 mg, 0.02 mmol; prepared according to Example 12), Cs₂CO₃ (15 mg,0.05 mmol) and 2nd Generation XPhos Precatalyst (1.9 mg, 2.4 μmol) in1,4-dioxane (2 mL) and water (0.5 mL) under nitrogen. The resultingmixture was warmed to 60° C. and maintained under these conditions for45 minutes. This reaction was then allowed to cool to r.t.

In a separate flask the remaining suspension mixture containing crude3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine(approximately 2.0 mL) was added to a mixture of(1S,3R)-3-acetamido-N-(5-chloro-4-iodopyridin-2-yl)cyclohexanecarboxamide(70 mg, 0.17 mmol; prepared according to Example 12), Cs₂CO₃ (325 mg,1.00 mmol) and 2nd Generation XPhos Precatalyst (26 mg, 0.03 mmol) in1,4-dioxane (16 mL) and water (4 mL) under nitrogen. The resultingmixture was stirred at 60° C. for 45 minutes. This reaction was thenallowed to cool to r.t.

Both cooled reaction mixtures were combined and then diluted withsaturated aqueous sodium chloride (100 mL). The resulting mixture wasextracted with EtOAc (3×100 mL), and the combined organic layers weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The resulting residue was purified by flash silica chromatography, usingan elution gradient of 0 to 100% EtOAc in petroleum ether followed by anelution gradient of 0 to 20% MeOH in EtOAc. Pure fractions wereconcentrated under reduced pressure. The resulting residue was furtherpurified by preparative HPLC (XBridge Prep C18 OBD column, 5a silica, 19mm diameter, 150 mm length), using decreasingly polar mixtures of water(containing 0.8% NH₄HCO₃) and MeCN as eluents. Fractions containing thedesired compound were concentrated under reduced pressure to afford(1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(20 mg, 25%) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz, 21° C.)1.00-1.14 (1H, m), 1.19-1.37 (3H, m), 1.68-1.81 (6H, m), 1.81-1.92 (3H,m), 1.99-2.10 (2H, m), 2.56-2.70 (1H, m), 2.82 (2H, t), 3.51-3.63 (1H,m), 4.42 (2H, t), 7.80 (1H, d), 8.26 (1H, s), 8.48 (1H, s), 10.73 (1H,s). m/z: ES+ [M+H]+ 417.

Example 50:(1S,3R)-3-acetamido-N-(4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide

Acetic anhydride (0.024 mL, 0.26 mmol) was added dropwise to(1S,3R)-3-amino-N-(4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide(0.080 g, 0.22 mmol), 4-dimethylaminopyridine (1 mg, 11 μmol) andtriethylamine (0.093 mL, 0.67 mmol) in DCM (2 mL) at r.t. undernitrogen. The resulting solution was stirred at r.t. for 4 h. Thereaction mixture was quenched with saturated aqueous ammonium chloride(10 mL), extracted with DCM (2×10 mL), and the combined organic layerswere dried over MgSO₄, filtered, and concentrated under reducedpressure. The resulting residue was purified by preparative HPLC (WatersXBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length),using decreasingly polar mixtures of water (containing 1% NH₃) and MeCNas eluents. Fractions containing the desired compound were concentratedunder reduced pressure to afford(1S,3R)-3-acetamido-N-(4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide(0.070 g, 79%). ¹H NMR (500 MHz, DMSO-d₆, 30° C.) 1.02-1.21 (1H, m),1.22-1.38 (9H, m), 1.70-1.82 (6H, m), 1.91 (1H, br d), 2.54-2.65 (1H,m), 2.71 (2H, s), 3.58 (1H, dt), 4.00 (2H, s), 7.44 (1H, d), 7.76 (1H,d), 8.34 (1H, d), 8.38 (1H, d), 10.56 (1H, s). m/z: ES+ [M+H]+ 414.

Procedures used to prepare the starting material to(1S,3R)-3-amino-N-(4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of3-(2-chloro-5-fluoropyridin-4-yl)-6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

6,6-Dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (0.180 g, 1.32 mmol;prepared according to Example 22), 2-chloro-5-fluoro-4-iodopyridine(0.476 g, 1.85 mmol), cesium carbonate (0.474 g, 1.45 mmol),triethylamine (0.368 mL, 2.64 mmol), triphenylphosphine (0.055 g, 0.21mmol) and diacetoxypalladium (0.024 g, 0.11 mmol) were suspended in1,4-dioxane (5 mL) and sealed into a microwave tube. The reaction wassubjected to microwave conditions (100° C., 16 h) and cooled to r.t. Thereaction mixture was diluted with DCM (20 mL) and washed with water(3×25 mL). The organic layer was then dried over MgSO₄, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby flash silica chromatography, elution gradient 0 to 50% EtOAc inheptane. Pure fractions were concentrated under reduced pressure toafford3-(2-chloro-5-fluoropyridin-4-yl)-6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole(0.185 g, 53%) as an orange solid. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.34(6H, s), 2.80 (2H, s), 3.93 (2H, s), 7.32 (1H, d), 7.59 (1H, d), 8.26(1H, d). m/z: ES+ [M+H]+ 266.

Preparation of tert-butyl((1R,3S)-3-((4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate

Tetrakis(triphenylphosphine)palladium(0) (43 mg, 0.04 mmol) was added to3-(2-chloro-5-fluoropyridin-4-yl)-6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole(100 mg, 0.38 mmol), tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate(109 mg, 0.45 mmol; prepared according to Example 25),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (44 mg, 0.08 mmol) andcesium carbonate (368 mg, 1.13 mmol) in 1,4-dioxane (6 mL). The mixturewas degassed for 5 minutes under nitrogen, and the resulting suspensionwas subjected to microwave conditions (120° C., 3 h). The reactionmixture was partitioned between water (20 mL) and DCM (40 mL). Thelayers were separated using a phase separation cartridge, and theorganic layer was adsorbed onto silica and purified by flash silicachromatography, elution gradient 0 to 60% EtOAc in heptane. Purefractions were concentrated under reduced pressure to afford tert-butyl((1R,3S)-3-((4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate(142 mg, 80%). m/z: ES+ [M+H]+ 472.

Preparation of(1S,3R)-3-amino-N-(4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide

Tert-butyl((1R,3S)-3-((4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.100 g, 0.21 mmol) was dissolved in DCM (5 mL) and trifluoroaceticacid (0.16 mL, 2.1 mmol) was added. The reaction mixture was stirred atr.t. for 30 min and then purified by ion exchange chromatography usingan SCX column. The desired product was eluted from the column using 1 MNH₃ in MeOH, and pure fractions were concentrated under reduced pressureto afford semipure(1S,3R)-3-amino-N-(4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-5-fluoropyridin-2-yl)[1,2-a]imidazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamideas a colourless gum (100 mg). This gum was used in next step withoutfurther purification. m/z: ES+ [M+H]+ 372.

Example 51:(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide

Acetic anhydride (0.088 mL, 0.93 mmol) was added to a stirred solutionof(1S,3R)-3-amino-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide(300 mg, 0.78 mmol; described in Example 51a), triethylamine (0.23 mL,1.6 mmol) and DCM (10 mL). The reaction mixture was stirred at ambienttemperature for 4 h. Silica was added, and the volatiles were removed byconcentration under reduced pressure. The resulting residue purified byflash silica chromatography, eluting with 0.5% methanol in ethylacetate, to afford(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide(300 mg, 90%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.) 1.03(6H, s), 1.02-1.14 (1H, m), 1.24-1.38 (3H, m), 1.72-1.81 (6H, m),1.86-1.91 (3H, m), 2.55-2.64 (1H, m), 2.69 (2H, s), 3.52-3.64 (1H, m),4.16 (2H, t), 7.64-7.81 (2H, m), 8.19 (1H, d), 8.29 (1H, d), 10.45 (1H,s). m/z: ES+ [M+H]+ 428.

Example 51a:(1S,3R)-3-amino-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide

TFA (2 mL) was added to a solution of tert-butyl((1R,3S)-3-((4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate(1.1 g, 2.27 mmol) in DCM (20 mL). The resulting mixture was stirred atambient temperature for 24 h, and then the reaction was concentratedunder reduced pressure. The resulting residue was purified by ionexchange chromatography using an SCX column. The desired product waseluted from the column using 7N NH₃ in MeOH. Pure product fractions wereconcentrated under reduced pressure to afford(1S,3R)-3-amino-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide(0.87 g, 100%) as a solid. ¹H NMR (400 MHz, CDCl₃, 22° C.) 1.01-1.12(7H, m), 1.31-1.49 (3H, m), 1.83-1.99 (5H, m), 2.14 (1H, d), 2.35 (1H,td), 2.66-2.85 (3H, m), 4.23 (2H, t), 7.85 (1H, d), 7.99-8.18 (2H, m),8.29 (1H, d). NH₂ signal not observed and is assumed to be under broadwater peak at 1.66 ppm. m/z: ES+ [M+H]+ 386.

Procedures for preparing the starting material of tert-butyl((1R,3S)-3-((4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamateare described below:

Preparation of5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine

Isopropylmagnesium chloride lithium chloride complex in THF (1.3 M; 9.1mL, 12 mmol) was added dropwise to3-iodo-5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (2.5 g,9.1 mmol; prepared according to Example 44) in THF (20 mL) undernitrogen at 0° C. The resulting mixture was stirred at 0° C. for 30minutes. Then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.8mL, 14 mmol) was added dropwise, and the ice bath was removed. Thereaction was maintained under these conditions for 18 h and then dilutedwith Et₂O (20 mL). This new mixture was washed sequentially withsaturated aqueous ammonium chloride (20 mL), water (20 mL), andsaturated aqueous sodium chloride (10 mL). The organic layer was driedover MgSO₄, filtered, and concentrated under reduced pressure to affordcrude5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(2.5 g, 100%) as an oil. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.06 (6H, s),1.29 (12H, s), 1.79 (2H, t), 2.74 (2H, s), 4.16 (2H, t), 7.72 (1H, s).

Preparation of3-(2-chloro-5-fluoropyridin-4-yl)-5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine

2-Chloro-5-fluoro-4-iodopyridine (1.55 g, 6.03 mmol),5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(2.0 g, 7.2 mmol), 2nd Generation XPhos Precatalyst (0.48 g, 0.60 mmol)and potassium phosphate, dibasic (3.15 g, 18.1 mmol) were dissolved indegassed dioxane (20 mL) and water (1 mL) at 21° C. The mixture wasstirred at 90° C. for 24 h and then allowed to cool to r.t. The mixturewas diluted with EtOAc (30 mL), washed with water (10 mL), and theorganic layer was concentrated under reduced pressure. The resultingresidue was purified by flash silica chromatography, elution gradient 0to 50% EtOAc in heptane. Pure fractions were concentrated under reducedpressure to afford3-(2-chloro-5-fluoropyridin-4-yl)-5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(1.3 g, 77%) as a white solid. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.10 (6H,s), 1.89 (2H, m), 2.68 (2H, s), 4.26 (2H, t), 7.27 (1H, d), 7.80 (1H,d), 8.23 (1H, d). m/z: ES+ [M+H]+ 280.

Preparation of tert-butyl((1R,3S)-3-((4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate

Tetrakis(triphenylphosphine)palladium(0) (0.496 g, 0.43 mmol) was addedto3-(2-chloro-5-fluoropyridin-4-yl)-5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(1.2 g, 4.29 mmol), tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate(1.04 g, 4.29 mmol; prepared according to Example 25),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.496 g, 0.86 mmol) andcesium carbonate (4.19 g, 12.9 mmol) in 1,4-dioxane (10 mL). Theresulting mixture was degassed for 5 mins under nitrogen and thensubjected to microwave conditions (120° C.; 17 h). The reaction mixturewas diluted with water (20 mL) and ethyl acetate (100 mL) before beingfiltered. The layers were separated, and the organic layer was adsorbedonto silica and purified by flash silica chromatography, eluting withisocratic 50% EtOAc in heptane. Pure fractions were concentrated underreduced pressure to afford tert-butyl((1R,3S)-3-((4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate(1.1 g, 53%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.) 1.03(6H, s), 1.02-1.14 (1H, m), 1.20-1.35 (3H, m), 1.39 (9H, s), 1.70-1.79(3H, br m), 1.82-1.92 (3H, m), 2.54-2.63 (1H, m), 2.68 (2H, s), 4.16(2H, t), 6.76 (1H, br d), 7.76 (1H, d), 8.19 (1H, d), 8.29 (1H, d),10.43 (1H, s). 1H multiplet under water peak. m/z: ES+ [M+H]+ 486.

Example 52:(1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(3-hydroxypropanamido)cyclohexanecarboxamide

Trifluoroacetic acid (6.5 μL, 0.080 mmol) was added to(1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propanamido)cyclohexanecarboxamide(0.046 g, 0.080 mmol) in DCM (2 mL) at r.t. The resulting solution wasstirred at r.t. for 1 hour. The crude product was purified by ionexchange chromatography, using an SCX column. The desired product waseluted from the column using 1 M NH₃ in MeOH and pure fractions wereconcentrated under reduced pressure to afford(1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(3-hydroxypropanamido)cyclohexanecarboxamide(0.032 g, 82%) as a colourless solid. ¹H NMR (400 MHz, CDCl₃, 30° C.)1.08-1.21 (1H, m), 1.34 (6H, s), 1.35-1.49 (3H, m), 1.88-1.93 (3H, m),2.10-2.37 (2H, m), 2.36-2.49 (2H, m), 2.48-2.57 (1H, m), 2.95 (2H, s),3.79-3.92 (3H, m), 3.95 (2H, s), 6.56 (1H, br d), 8.09 (1H, s), 8.21(1H, s), 8.26 (1H, s), 8.89 (1H, s). m/z: ES+ [M+H]+ 460.

Procedures for preparing the starting material(1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propanamido)cyclohexanecarboxamideare described below:

Preparation of methyl 3-hydroxypropanoate

Oxetan-2-one (22 mL, 350 mmol) was added dropwise to a stirred solutionof MeOH (300 mL) and sulfuric acid (5.6 mL, 104 mmol) at 0° C. After 18h, the reaction was recooled to 10° C., and sodium bicarbonate (18.1 g,215 mmol) was added portionwise (pH=7 after addition). The resultingsuspension was left to stir at r.t. for 30 minutes. The mixture was thenfiltered, and the filtrate was concentrated under reduced pressure. Theresulting residue was diluted with DCM and filtered a second time. Thenew filtrate was evaporated to dryness to afford methyl3-hydroxypropanoate (35 g, 97%) as a colorless liquid. ¹H NMR (500 MHz,CDCl₃, 24° C.) 2.41-2.45 (1H, m), 2.58 (2H, t), 3.72 (3H, s), 3.89 (2H,t).

Preparation of methyl 3-(tetrahydro-2H-pyran-2-yloxy)propanoate

Pyridine 4-methylbenzenesulfonate (4.22 g, 16.8 mmol) was added to asolution of methyl 3-hydroxypropanoate (35 g, 336 mmol) and3,4-dihydro-2H-pyran (43 mL, 470 mmol) in DCM (500 ml) under nitrogen.The solution was stirred at r.t. for 2.5 days. The mixture was thenwashed with a saturated aqueous sodium bicarbonate, and the organiclayer was dried over magnesium sulfate and concentrated under reducedpressure. The resulting oil was purified by flash silica chromatography,eluting with isocratic 15% ethyl acetate in heptane, to afford methyl3-(tetrahydro-2H-pyran-2-yloxy)propanoate (26 g, 41%) as a colorlessoil. ¹H NMR (500 MHz, DMSO-d₆, 24° C.) 1.37-1.46 (4H, m), 1.54-1.59 (2H,m), 2.56 (2H, t), 3.39-3.42 (1H, m), 3.53-3.63 (4H, m), 3.68-3.75 (1H,m), 3.81-3.87 (1H, m), 4.57 (1H, t).

Preparation of 3-(tetrahydro-2H-pyran-2-yloxy)propanoic acid

Aqueous sodium hydroxide (2N; 134 mL, 268 mmol) was added to a solutionof methyl 3-(tetrahydro-2H-pyran-2-yloxy)propanoate (26 g, 138 mmol) inTHF (300 mL). The mixture was stirred at r.t. for 5 h and thenconcentrated under reduced pressure. Ethyl acetate (100 mL) was added,and the layers were separated. The aqueous layer was cooled to 0° C.,and aqueous HCl (1N) was cautiously added dropwise until a pH of 3.5 wasachieved. The aqueous layer was then extracted with ethyl acetate (2×250mL). The combined organic layers were dried over magnesium sulfate,filtered and concentrated under reduced pressure to afford3-(tetrahydro-2H-pyran-2-yloxy)propanoic acid (24 g, 98%) as a colorlessoil. ¹H NMR (500 MHz, CDCl₃, 24° C.) 1.45-1.62 (4H, m), 1.63-1.85 (2H,m), 2.64-2.68 (2H, m), 3.52-3.56, (1H, m), 3.70-3.74, (1H, m), 3.85-3.89(1H, m), 3.99-4.03 (1H, m), 4.62-4.66 (1H, m), 11.2 (1H, br s).

Preparation of(1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propanamido)cyclohexanecarboxamide

HATU (118 mg, 0.31 mmol) was added to a solution of3-((tetrahydro-2H-pyran-2-yl)oxy)propanoic acid (54 mg, 0.31 mmol),(1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(100 mg, 0.26 mmol; prepared according to Example 14), and triethylamine(0.11 mL, 0.77 mmol) in DMA (2 mL). The resulting mixture was stirred atambient temperature for 16 h before HCl in dioxane (4 M; 0.52 mL, 2.1mmol) was added. This new mixture was stirred at r.t. for 2 h beforebeing basified with saturated aqueous Na₂CO₃. The resulting mixture wasdiluted with water (20 mL) and extracted with DCM (50 mL). The organiclayer was washed with saturated aqueous sodium chloride (50 mL) beforebeing passed through a phase separation cartridge. The organic fractionswere dried over MgSO₄ and concentrated under reduced pressure. Theresulting residue was purified by preparative HPLC (Waters XBridge PrepC18 OBD column, 5p silica, 30 mm diameter, 100 mm length), usingdecreasingly polar mixtures of water (containing 1% NH₃) and MeCN aseluents. Fractions containing the desired compound were concentratedunder reduced pressure to afford(1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propanamido)cyclohexanecarboxamide(46 mg, 33%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆, 30° C.)1.05-1.2 (1H, m), 1.24-1.51 (13H, m), 1.52-1.63 (1H, m), 1.64-1.71 (1H,m), 1.72-1.83 (3H, m), 1.88-1.93 (1H, m), 2.25-2.35 (2H, m), 2.57-2.7(1H, m), 2.90 (2H, s), 3.38-3.44 (1H, m), 3.48-3.58 (1H, m), 3.59-3.64(1H, m), 3.74 (1H, ddd), 3.81 (1H, ddt), 3.95 (2H, s), 4.55 (1H, d),7.78 (1H, d), 8.00 (1H, s), 8.25 (1H, s), 8.36 (1H, s), 10.56 (1H, s).m/z: ES+ [M+H]+ 544.

Example 53:(1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(cis-3-hydroxycyclobutanecarboxamido)cyclohexanecarboxamide

HATU (118 mg, 0.31 mmol) was added to a solution ofcis-3-((tert-butyldimethylsilyl)oxy)cyclobutanecarboxylic acid (71 mg,0.31 mmol; prepared according to Example 4),(1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(100 mg, 0.26 mmol; prepared according to Example 14), and triethylamine(0.11 mL, 0.77 mmol) in DMA (2 mL). The resulting mixture was stirred atr.t. for 16 h before a solution of tetrabutylammonim fluoride in THF (1M; 1.0 mL, 1.0 mmol) was added. The mixture was stirred at r.t. for 2 hbefore being quenched with water (20 mL). The mixture was extracted withDCM (50 mL) and washed with saturated aqueous sodium chloride (50 mL)before being passed through a phase separation cartridge. The organicfractions were dried over MgSO₄ and concentrated under reduced pressure.The resulting residue was purified by preparative HPLC (Waters XBridgePrep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), usingdecreasingly polar mixtures of water (containing 1% NH₃) and MeCN aseluents. Product fractions were concentrated under reduced pressure, andthe resulting residue was further purified by flash silicachromatography, elution gradient 0 to 10% MeOH in EtOAc. Pure fractionswere concentrated under reduced pressure to afford(1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-((cis)-3-hydroxycyclobutanecarboxamido)cyclohexanecarboxamide(0.037 g, 53%) as a white solid. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.34(6H, s), 1.47-1.49 (3H, m), 1.85-1.99 (5H, m), 2.10-2.30 (4H, m),2.39-2.62 (4H, m), 2.96 (2H, s), 3.79-3.86 (1H, m), 3.95 (2H, s), 5.90(1H, br d), 8.09 (1H, s), 8.22 (1H, s), 8.26 (1H, s), 8.69 (1H, s). m/z:ES+ [M+H]+ 486.

Example 54:(1S,3R)-3-amino-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide

Hydrochloric acid in dioxane (4 M; 3.2 mL, 13 mmol) was added to asolution of tert-butyl((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate(600 mg, 1.27 mmol) in DCM (9.5 mL) to give a yellow suspension.Methanol (˜5 mL) was added, which afforded a clear yellow solution. Thereaction was stirred for 18 h at r.t. and then concentrated underreduced pressure to afford(1S,3R)-3-amino-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamideas a dihydrochloride salt (488 mg, 87%) and an off-white solid. ¹H NMR(300 MHz, DMSO-d₆, 27° C.) 1.23-1.36 (9H, m), 1.50 (1H, q), 1.77-1.89(2H, m), 1.89-2.01 (1H, m), 2.01-2.09 (1H, m), 2.56-2.68 (1H, m), 2.94(2H, s), 2.97-3.09 (1H, m), 3.95 (2H, s), 7.85-7.93 (1H, m), 7.98-8.14(3H, m), 8.26-8.32 (2H, m), 10.56 (1H, s). 1 HCl equivalent assumed tobe incorporated into broad singlet at 5.4 ppm. m/z: ES+ [M+H]+ 372.

Procedures used to prepare the starting material tert-butyl((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamateare described below:

Preparation of 5-fluoro-4-iodopyridin-2-amine

Concentrated aqueous ammonium hydroxide (26 wt %; 7.0 mL, 45 mmol) wasadded dropwise (slight exotherm) to a solution of2,5-difluoro-4-iodopyridine (2.0 g, 8.30 mmol) in DMSO (2 mL) to give awhite suspension. The suspension was heated in the microwave at 140° C.for 4 h. The reaction was partitioned between EtOAc and water, and theaqueous layer was extracted with EtOAc (3×50 mL). The combined organicswere concentrated under reduced pressure, and the resulting residue wasadsorbed onto silica gel before being purified by flash silicachromatography (0 to 10% methanol in DCM) to afford5-fluoro-4-iodopyridin-2-amine (1.3 g, 66%) as a white solid. ¹H NMR(300 MHz, DMSO-d₆, 27° C.) 5.96 (1H, br s) 5.96 (1H, s) 6.92 (1H, d)7.77-7.84 (1H, m). m/z: ES+ [M+H]+ 239.

Tert-butyl((1R,3S)-3-((5-fluoro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate

1-Chloro-N,N,2-trimethylprop-1-en-1-amine (0.62 mL, 4.7 mmol) was addedto a solution of(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (843mg, 3.47 mmol; prepared according to Example 2) in DCM (15 mL). Thecolorless solution was stirred at r.t. for 1.5 h. Then a solution of5-fluoro-4-iodopyridin-2-amine (750 mg, 3.15 mmol) and pyridine (0.51mL, 6.3 mmol) in DCM (15 mL) was added. The resulting reaction wasstirred at r.t. for 18 h before being diluted with DCM (200 mL) andwashed with water and saturated aqueous sodium chloride. The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. The resulting residue was adsorbed onto silica gel andpurified by flash silica chromatography, elution gradient 0 to 10%methanol in DCM, to afford tert-butyl((1R,3S)-3-((5-fluoro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate(827 mg, 57%) as a white solid. H NMR (300 MHz, DMSO-d₆, 27° C.)1.01-1.19 (1H, m), 1.18-1.31 (3H, m), 1.38 (9H, s), 1.61-1.81 (m, 3H),1.87 (1H, d), 2.53-2.62 (1H, m), 3.16-3.26 (1H, m), 6.78 (1H, br d),8.26 (1H, s), 8.60 (1H, d), 10.61 (1H, s). m/z: ES+ [M+Na+]+486.

Preparation of tert-butyl((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate

Cesium carbonate (2.81 g, 8.61 mmol) and 2nd Generation XPhosPrecatalyst (0.090 g, 0.11 mmol) were added to a degassed mixture of5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(0.828 g, 3.16 mmol; prepared according to Example 23), tert-butyl((1R,3S)-3-((5-fluoro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate(1.33 g, 2.87 mmol), dioxane (24 mL), and water (5 mL). The reaction washeated to 95° C. and maintained under these conditions for 18 h. Thereaction was then diluted with EtOAc (250 mL), and washed with water andsaturated aqueous sodium chloride before being dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Theresulting residue was adsorbed onto silica gel and purified by flashsilica chromatography, elution gradient 0 to 100% ethyl acetate inhexanes, to afford tert-butyl((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate(600 mg, 44%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.03-1.15 (1H, obsc. m), 1.22-1.32 (9H, m), 1.38 (9H, s), 1.69-1.82 (3H,m), 1.89 (1H, br d) 2.53-2.64 (1H, m), 2.93 (2H, s), 3.21-3.32 (1H, m),3.96 (2H, s), 6.78 (1H, d), 7.88 (1H, d), 8.27 (1H, d), 8.31 (1H, d),10.45 (1H, s). m/z: ES+ [M+H]+ 472.

Example 55:(1S,3R)—N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide

HATU (98 mg, 0.26 mmol) was added to a solution of1-hydroxycyclopropanecarboxylic acid (32 mg, 0.31 mmol),(1S,3R)-3-amino-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamidedihydrochloride (96 mg, 0.22 mmol; prepared according to Example 54),and triethylamine (0.11 mL, 0.77 mmol) in DMF (1.5 mL). The reactionmixture was heated at 50° C. for 1.75 h and then allowed to cool to r.t.After 18 h, the resulting mixture was purified by preparative HPLC(Waters XBridge Prep C18 OBD column, 5a silica, 30 mm diameter, 100 mmlength) using decreasingly polar mixtures of water (containing 1% NH₃)and MeCN as eluents. Fractions containing the desired compound wereevaporated to dryness to afford(1S,3R)—N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide(33 mg, 33%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆, 30° C.)0.76-0.84 (2H, m), 0.98-1.04 (2H, m), 1.29 (6H, s), 1.30-1.37 (3H, m),1.52 (1H, q), 1.7-1.84 (3H, m), 1.88 (1H, d), 2.58-2.67 (1H, m), 2.94(2H, s), 3.63-3.73 (1H, m), 3.95 (2H, s), 6.14 (1H, br s), 7.65 (1H, d),7.89 (1H, d), 8.28 (1H, d), 8.32 (1H, d), 10.46 (1H, s). m/z: ES+ [M+H]+456.

Example 56:(1S,3R)—N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide

HATU (118 mg, 0.31 mmol) was added to a solution of1-hydroxycyclopropanecarboxylic acid (31.6 mg, 0.31 mmol),(1S,3R)-3-amino-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(100 mg, 0.26 mmol), and triethylamine (0.11 mL, 0.77 mmol) in DMA (2mL). The reaction was stirred overnight at r.t. and was then purified bypreparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mmdiameter, 100 mm length), using decreasingly polar mixtures of water(containing 1% NH₃) and MeCN as eluents. Fractions containing thedesired compound were concentrated under reduced pressure to afford(1S,3R)—N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide(27 mg, 22%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆, 30° C.)0.75-0.82 (2H, m), 0.93-1.09 (2H, m), 1.25 (6H, s), 1.27-1.38 (3H, m),1.52 (1H, q), 1.65-1.93 (4H, m), 2.53-2.70 (1H, m), 2.71 (2H, s),3.60-3.71 (1H, m), 3.91 (2H, s), 6.15 (1H, s), 7.51 (1H, s), 7.65 (1H,d), 8.29 (1H, s), 8.42 (1H, s), 10.65 (1H, s). m/z: ES+ [M+H]+ 472.

Procedures used to prepare the starting material(1S,3R)-3-amino-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of tert-butyl((1R,3S)-3-((5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate

Tert-butyl((1R,3S)-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.40 g, 0.83 mmol; prepared according to Example 10),6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (0.200 g, 1.25 mmol;prepared according to Example 22), potassium acetate (0.163 g, 1.66mmol) and palladium acetate (0.337 g, 0.33 mmol) were suspended in DMA(10 mL) and sealed into a microwave tube. The tube was evacuated andpurged with nitrogen (3×) and then heated at 150° C. for 16 h. Thereaction mixture was purified by ion exchange chromatography using anSCX column. The desired product was eluted from the column using 1 M NH₃in MeOH, and pure fractions were concentrated under reduced pressure.The resulting residue was purified by flash silica chromatography,elution gradient 0 to 100% EtOAc in heptane. Pure fractions wereconcentrated under reduced pressure to afford tert-butyl((1R,3S)-3-((5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.20 g, 49%) as an orange gum. ¹H NMR (400 MHz, CDCl₃, 21° C.)1.05-1.19 (1H, m), 1.33 (6H, s), 1.40-1.46 (12H, m), 1.9-2.05 (3H, m),2.20-2.47 (2H, m), 2.78 (2H, s), 3.46-3.52 (1H, m), 3.93 (2H, s),4.44-4.52 (1H, m), 7.67 (1H, s), 8.06 (1H, br s), 8.28 (1H, s), 8.29(1H, s). m/z: ES+ [M+H]+ 488.

Preparation of(1S,3R)-3-amino-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Tert-butyl((1R,3S)-3-((5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.25 g, 0.51 mmol) was dissolved in DCM (5 mL). Trifluoroacetic acid(0.39 mL, 5.1 mmol) was added, and the reaction mixture stirred at r.t.for 30 min. The reaction mixture was then purified by ion exchangechromatography using an SCX column. The desired product was eluted fromthe column using 1 M NH₃ in MeOH, and pure fractions were concentratedunder reduced pressure to afford(1S,3R)-3-amino-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.19 g, 96%) as an orange gum. This gum was used in the next stepwithout further purification. m/z: ES+ [M+H]+ 388.

Example 57:N-((1R,3S)-3-((5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide

HATU (118 mg, 0.31 mmol) was added to a solution of oxetane-3-carboxylicacid (32 mg, 0.31 mmol),(1S,3R)-3-amino-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(100 mg, 0.26 mmol; prepared according to Example 56) and triethylamine(0.11 mL, 0.77 mmol) in DMA (2 mL). The reaction mixture was purified bypreparative HPLC (Waters XBridge Prep C18 OBD column, 5p silica, 30 mmdiameter, 100 mm length), using decreasingly polar mixtures of water(containing 1% NH₃) and MeCN as eluents. Fractions containing thedesired compound were concentrated under reduced pressure to affordsemipure product. This material was further purified by flash silicachromatography, elution gradient 0 to 10% MeOH in EtOAc. Pure fractionswere concentrated under reduced pressure to affordN-((1R,3S)-3-((5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide(13 mg, 11%) as a white solid. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.11-1.29(1H, m), 1.32 (6H, s), 1.36-1.6 (3H, m), 1.9-2.02 (3H, m), 2.22-2.31(1H, br d), 2.41-2.55 (1H, m), 2.78 (2H, s), 3.67 (1H, ddd), 3.82-3.96(3H, m), 4.74-4.9 (4H, m), 5.75 (1H, d), 7.64 (1H, s), 8.27 (3H, d).m/z: ES+ [M+H]+ 472.

Example 58:cis-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide

Cis-3-((tert-butyldimethylsilyl)oxy)-N-(5-chloro-4-iodopyridin-2-yl)cyclobutanecarboxamide(0.194 g, 0.42 mmol; prepared according to Example 27),6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (0.100 g, 0.62 mmol;prepared according Example 22), potassium acetate (0.082 g, 0.83 mmol)and palladium acetate (0.168 g, 0.17 mmol) were suspended in DMA (10 mL)and sealed into a microwave tube. The tube was evacuated and purged withnitrogen (3×) and then heated at 150° C. for 16 h. The reaction mixturewas diluted with water (20 mL) and washed with DCM (3×20 mL). Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19mm diameter, 100 mm length), using decreasingly polar mixtures of water(containing 1% NH₃) and MeCN as eluents. Product fractions wereconcentrated under reduced pressure, and the resulting residue wasrepurified by preparative HPLC (Waters SunFire column, 5μ silica, 19 mmdiameter, 100 mm length), using decreasingly polar mixtures of water(containing 0.1% formic acid) and MeCN as eluents. Fractions containingthe desired compound were concentrated under reduced pressure to affordcis-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide(0.016 g, 11%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆, 30° C.) 1.26(6H, s), 1.98-2.09 (2H, m), 2.30-2.40 (2H, m), 2.72 (2H, s), 2.74-2.83(1H, m), 3.93 (2H, s), 3.95-4.00 (1H, m), 5.15 (1H, s), 7.53 (1H, s),8.32 (1H, s), 8.41 (1H, s), 10.61 (1H, s). m/z: ES+ [M+H]+ 361.

Example 59 and 60: Isomer 1 and Isomer 2 oftrans-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Examples 59 and 60 are Pure Enantiomers with Relative TransConfigurations

The absolute configurations of Examples 59 and 60 are unknown but areopposite from one another.

Acetic anhydride (0.049 mL, 0.52 mmol) was added dropwise totrans-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.167 g, 0.43 mmol), 4-dimethylaminopyridine (2.6 mg, 0.02 mmol) andtriethylamine (0.19 mL, 1.3 mmol) in DCM (2 mL) at r.t. under nitrogen.The resulting solution was stirred at r.t. for 4 h. The reaction mixturewas quenched with saturated aqueous ammonium chloride (10 mL), extractedwith DCM (2×10 mL), and the combined organic layers were dried overMgSO₄, filtered, and concentrated under reduced pressure. The resultingresidue was purified by preparative HPLC (Chiral Technologies IE column,20 m silica, 50 mm diameter, 250 mm length) eluting with isocratic 30%heptane in acetone at 120 mL/min with detection at 210 nm. Fractionscontaining the desired compounds were concentrated under reducedpressure to afford faster eluting isomer 1 oftrans-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.059 g, 32%) and slower eluting isomer 2 oftrans-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.052 g, 28%) as white solids.

Example 59, Isomer 1

¹H NMR (400 MHz, CDCl₃, 30° C.) 1.34 (6H, s), 1.56-2.00 (8H, m), 2.01(3H, s), 2.48-2.56 (1H, m), 2.96 (2H, s), 3.95 (2H, s), 4.17-4.24 (1H,m), 5.42-5.49 (1H, m), 7.96 (1H, br s), 8.10 (1H, s), 8.24 (1H, s), 8.26(1H, s). m/z: ES+ [M+H]+ 430.

Example 60, Isomer 2

¹H NMR (400 MHz, CDCl₃, 30° C.) 1.34 (6H, s), 1.48-1.55 (1H, m),1.62-1.78 (4H, m), 1.82-1.90 (1H, m), 1.94-1.98 (2H, m), 2.01 (3H, s),2.46-2.58 (1H, m), 2.96 (2H, s), 3.95 (2H, s), 4.17-4.26 (1H, m),5.45-5.54 (1H, br d), 8.01 (1H, s), 8.10 (1H, s), 8.23 (1H, s), 8.26(1H, s). m/z: ES+ [M+H]+ 430.

Analytical Reverse Phase Chiral Conditions:

Column: Chiral Technologies IE column

Column Dimensions: 5 μm, 4.6 mm diameter, 250 mm length

Mobile Phase A: Acetonitrile

Mobile Phase B: MeOH

Gradient: Isocratic 10% Mobile Phase B

Flow Rate: 1 mL/min over 30 min

Retention Time: 4.9 min, Example 59

-   -   6.3 min, Example 60        e.e. >98%, Example 59    -   >98%, Example 60

Procedures used to prepare the starting material totrans-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of tert-butyltrans-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate

1-Chloro-N,N,2-trimethylprop-1-en-1-amine (1.1 mL, 8.2 mmol) was addedto trans-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (1.34g, 5.50 mmol) in DCM (20 mL) at 0° C. under nitrogen. The resultingsolution was stirred at 20° C. for 1.5 h, and then5-chloro-4-iodopyridin-2-amine (1.40 g, 5.50 mmol; prepared according toExample 2) and pyridine (0.67 mL, 8.2 mmol) were added dropwise over 2minutes. The resulting solution was stirred for 70 h. The reactionmixture was then quenched with saturated aqueous sodiumhydrogencarbonate (300 mL), extracted with DCM (3×30 mL), and thecombined organic layers were dried over MgSO₄, filtered, andconcentrated under reduced pressure to afford a cream-colored solid.This solid was purified by preparative HPLC (Waters XBridge Prep C18 OBDcolumn, 5μ silica, 30 mm diameter, 100 mm length), using decreasinglypolar mixtures of water (containing 1% NH₃) and MeCN as eluents.Fractions containing the desired compound were concentrated underreduced pressure to afford tert-butyl(trans-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.99 g, 37%) as a pink solid. ¹H NMR (500 MHz, CDCl₃, 27° C.) 1.46 (9H,s), 1.49-1.55 (1H, m), 1.61-1.72 (4H, m), 1.82-1.93 (3H, m), 2.47-2.52(1H, m), 3.89-3.99 (1H, br s), 4.55-4.59 (1H, br s), 7.84 (1H, br s),8.19 (1H, s), 8.83 (1H, s). m/z: ES+ [M+H]+ 480.

Preparation of tert-butyl(trans-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate

2nd Generation XPhos Precatalyst (0.049 g, 0.06 mmol) was added to adegassed mixture of5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(0.219 g, 0.75 mmol; prepared according to Example 23), tert-butyl(trans-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.30 g, 0.63 mmol) and potassium phosphate, tribasic, (0.327 g, 1.88mmol) in 1,4-dioxane (8 mL) and water (1.6 mL). The mixture was degassedand stirred at 90° C. for 2 h under nitrogen. The reaction mixture wasthen concentrated under reduced pressure and taken up in water (20 mL).The resulting mixture was extracted sequentially with EtOAc (2×20 mL)and DCM (20 mL). The combined organic layers were dried over MgSO₄,filtered, and concentrated under reduced pressure. The resulting residuewas purified by flash silica chromatography, elution gradient 0 to 70%EtOAc in heptane. Product fractions were concentrated under reducedpressure to afford tert-butyl(trans-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.26 g, 86%) as a cream-colored solid. m/z: ES+ [M+H]+ 488.

Preparation oftrans-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Tert-butyl(trans-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.263 g, 0.54 mmol) was dissolved in DCM (5 mL). Trifluoroacetic acid(0.41 mL, 5.4 mmol) was added, and the reaction mixture was stirred atr.t. for 18 h. The reaction was then purified by ion exchangechromatography, using an SCX column. The desired product was eluted fromthe column using 1 M NH₃ in MeOH, and product fractions wereconcentrated under reduced pressure to affordtrans-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b][1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamideas a white solid. m/z: ES+ [M+H]+ 388.

Examples 61 and 62: Isomer 1 and Isomer 2 oftrans-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Examples 61 and 62 are Pure Enantiomers with Relative TransConfigurations

The absolute configurations of Examples 61 and 62 are unknown but areopposite from one another.

Acetic anhydride (0.036 mL, 0.38 mmol) was added dropwise totrans-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.119 g, 0.32 mmol), 4-dimethylaminopyridine (1.9 mg, 0.02 mmol), andtriethylamine (0.14 mL, 1.0 mmol) in DCM (2 mL) at r.t. under nitrogen.The resulting solution was stirred at r.t. for 4 h. The reaction mixturewas quenched with saturated aqueous ammonium chloride (10 mL), extractedwith DCM (2×10 mL), the combined organic layers were dried over MgSO₄,filtered, and concentrated under reduced pressure. The resulting residuewas purified by preparative HPLC (Chiral Technologies IE column, 20 amsilica, 50 mm diameter, 250 mm length), using a 30/70 mixture ofheptane/acetone as eluents, a flow rate of 120 mL/min, and a detectiontrigger at 210 nm. Fractions containing the desired compounds wereconcentrated under reduced pressure to afford faster eluting isomer 1 oftrans-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.076 g, 57%) and slower eluting isomer 2 oftrans-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.056 g, 42%).

Example 61, Isomer 1

¹H NMR (400 MHz, CDCl₃, 31° C.) 1.57-1.96 (7H, m), 2.01 (3H, s),2.04-2.16 (2H, m), 2.49-2.56 (1H, m), 2.92 (2H, t), 4.16-4.23 (3H, m),5.46-5.52 (1H, m), 7.87 (1H, s), 8.05 (1H, br s), 8.21 (1H, s), 8.27(1H, s). 3H at 1.50 to 1.62 ppm obscured by water signal. m/z: ES+[M+H]+ 416.

Example 62, Isomer 2

¹H NMR (400 MHz, CDCl₃, 30° C.) 1.45-1.96 (10H, m), 2.01 (3H, s),2.04-2.13 (2H, m), 2.49-2.58 (1H, m), 2.92 (2H, t), 4.16-4.24 (3H, m),5.52-5.57 (1H, m), 7.87 (1H, s), 8.12 (1H, br s), 8.21 (1H, s), 8.26(1H, s). m/z: ES+ [M+H]+ 416.

Analytical Reverse Phase Chiral Conditions:

Column: Chiral Technologies IE column

Column Dimensions: 5 μm, 4.6 mm diameter, 250 mm length

Mobile Phase A: Acetonitrile

Mobile Phase B: MeOH

Gradient: Isocratic 10% Mobile Phase B

Flow Rate: 1 mL/min over 30 min

Retention Time: 5.2 min, Example 61

-   -   6.8 min, Example 62        e.e. >98%, Example 61    -   >98%, Example 62

Procedures used to prepare the starting materialtrans-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of tert-butyl(trans-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate

2nd Generation XPhos Precatalyst (0.049 g, 0.06 mmol) was added to adegassed mixture of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(0.186 g, 0.75 mmol), tert-butyl(trans-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.30 g, 0.63 mmol; prepared according to Examples 59 and 60,Intermediates) and tribasic potassium phosphate (0.327 g, 1.88 mmol) in1,4-dioxane (10 mL) and water (2 mL). The reaction mixture was degassedand then stirred at 90° C. for 2 h under nitrogen. The reaction mixturewas concentrated under reduced pressure and taken up in water (20 mL).The resulting mixture was extracted sequentially with EtOAc (2×20 mL)and DCM (20 mL). The combined organic layers were dried over MgSO₄,filtered, and concentrated under reduced pressure. The resulting residuewas purified by flash silica chromatography, elution gradient 0 to 70%EtOAc in heptane. Pure fractions were concentrated under reducedpressure to afford tert-butyl(trans-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.163 g, 55%) as a cream-colored solid. ¹H NMR (500 MHz, CDCl₃, 27° C.)1.46 (9H, s), 1.48-1.54 (1H, m), 1.61-1.74 (4H, m), 1.82-1.97 (5H, m),2.05-2.13 (2H, m), 2.46-2.57 (1H, m), 2.92 (2H, t), 3.98 (1H, br s),4.21 (2H, t), 4.60 (1H, br s), 7.87 (2H, s), 8.21 (1H, s), 8.27 (1H, s).m/z: ES+ [M+H]+ 474.

Preparation oftrans-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Tert-butyl(trans-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.16 g, 0.34 mmol) was dissolved in DCM (5 mL). Trifluoroacetic acid(0.26 mL, 3.4 mmol) was added, and the reaction mixture was stirred atr.t. for 18 h. The reaction mixture was then purified by ion exchangechromatography, using an SCX column. The desired product was eluted fromthe column using 1 M NH₃ in MeOH, and product fractions wereconcentrated under reduced pressure to affordtrans-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamideas a yellow gum. m/z: ES+ [M+H]+ 374.

Example 63:(1S,3R)-3-acetamido-N-(5-fluoro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Acetic anhydride (0.032 mL, 0.34 mmol) was added to(1S,3R)-3-amino-N-(5-fluoro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.10 g, 0.28 mmol), triethylamine (0.12 mL, 0.84 mmol) andN,N-dimethylpyridin-4-amine (2 mg, 0.01 mmol) in DCM (5 mL) at r.t.under air. The resulting solution was stirred at r.t. for 2 h. Thereaction mixture was quenched with saturated aqueous ammonium chloride(20 mL) and extracted with DCM (2×20 mL). The combined organic layerswere dried over MgSO₄, filtered, and concentrated under reducedpressure. The resulting residue was purified by preparative HPLC (WatersXBridge Prep C18 OBD column, 5p silica, 30 mm diameter, 100 mm length),using decreasingly polar mixtures of water (containing 1% NH₃) and MeCNas eluents. Fractions containing the desired compound were concentratedunder reduced pressure to afford(1S,3R)-3-acetamido-N-(5-fluoro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.047 g, 42%) as a gum. 1H NMR (500 MHz, DMSO-d₆, 30° C.) 1.03-1.15(1H, m), 1.23-1.37 (3H, m), 1.74-1.82 (6H, m), 1.83-1.94 (3H, m),2.00-2.08 (2H, m), 2.56-2.68 (1H, m), 2.91 (2H, t), 3.58-3.61 (1H, m),4.15 (2H, t), 7.73-7.78 (2H, m), 8.26 (1H, d), 8.30 (1H, d), 10.48 (1H,s). m/z: ES+ [M+H]+ 400.

Procedures for preparing the starting material(1S,3R)-3-amino-N-(5-fluoro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of3-(2-chloro-5-fluoropyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine

2nd Generation XPhos Precatalyst (0.092 g, 0.12 mmol) was added to adegassed mixture of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(0.347 g, 1.40 mmol), 2-chloro-5-fluoro-4-iodopyridine (0.300 g, 1.17mmol) and potassium phosphate, tribasic (0.609 g, 3.50 mmol) in1,4-dioxane (10 mL) and water (2 mL). The mixture was degassed andstirred at 90° C. for 2 h under nitrogen. The reaction mixture wasconcentrated under reduced pressure, and the resulting residue was takenup in water (20 mL). The resulting mixture was extracted sequentiallywith DCM (3×20 mL). The organic layer was dried over MgSO₄, filtered,and concentrated under reduced pressure. The resulting residue waspurified by flash silica chromatography, elution gradient 0 to 60% EtOAcin heptane. Pure fractions were concentrated under reduced pressure toafford3-(2-chloro-5-fluoropyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(200 mg, 68%) as a yellow gum. m/z: ES+ [M+H]+ 252.

Preparation of tert-butyl((1R,3S)-3-((5-fluoro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate

Tetrakis(triphenylphosphine)palladium(0) (0.092 g, 0.080 mmol) was addedto a mixture of3-(2-chloro-5-fluoropyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(0.20 g, 0.79 mmol), tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate(0.231 g, 0.95 mmol; prepared according to Example 25),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.092 g, 0.16 mmol),and cesium carbonate (0.777 g, 2.38 mmol) in 1,4-dioxane (6 mL). Themixture was degassed (vacuum), backfilled with nitrogen, and theresulting suspension was stirred at 120° C. for 2 h in the microwavereactor. The reaction mixture was partitioned between water (20 mL) andDCM (40 mL) and separated using a phase separation cartridge. Theorganics were adsorbed onto silica and purified by flash silicachromatography, elution gradient 0 to 60% EtOAc in heptane. Fractionscontaining product were concentrated under reduced pressure to affordtert-butyl((1R,3S)-3-((5-fluoro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(136 mg). This material was used directly in the next step withoutfurther purification. m/z: ES+ [M+H]+ 458.

Preparation of(1S,3R)-3-amino-N-(5-fluoro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Trifluoroacetic acid (0.17 mL, 2.2 mmol) was added to tert-butyl((1R,3S)-3-((5-fluoro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.10 g, 0.22 mmol) in DCM (5 mL). The resulting solution was stirred atr.t. for 1 h. The crude product was purified by ion exchangechromatography using an SCX column. The desired product was eluted fromthe column using 1 M NH₃ in MeOH, and pure fractions were concentratedunder reduced pressure to afford(1S,3R)-3-amino-N-(5-fluoro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamideas a yellow gum. This material was used directly in the next stepwithout further purification. m/z: ES+ [M+H]+ 358.

Example 64 and 65: Preparation of isomer 1 and isomer 2 of(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Pure Enantiomers

The configuration of the methyl is unknown for Example 64 and 65 but isopposite in Example 64 vs Example 65.

2nd Generation XPhos precatalyst (0.056 g, 0.07 mmol) was added to amixture of5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(0.56 g, 0.85 mmol),(1S,3R)-3-acetamido-N-(5-chloro-4-iodopyridin-2-yl)cyclohexanecarboxamide(0.30 g, 0.71 mmol; prepared according to Example 12) and Cs₂CO₃ (0.695g, 2.13 mmol) in dioxane (10 mL) and water (2.0 mL) under nitrogen. Theresulting mixture was stirred at 100° C. for 30 minutes. The reactionmixture was then concentrated under reduced pressure, and the resultingresidue was diluted with DCM (100 mL) before being washed sequentiallywith water (100 mL) and saturated aqueous sodium chloride (100 mL). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 10% MeOH in DCM. Product fractionswere concentrated under reduced pressure, and the resulting residue wasfurther purified by preparative HPLC (Waters XBridge Prep C18 OBDcolumn, 5μ silica, 19 mm diameter, 150 mm length), using decreasinglypolar mixtures of water (containing 0.1% NH₄HCO₃) and MeCN as eluents.Product fractions were concentrated under reduced pressure to afford(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.120 g, 39%; mixture of Examples 64 and 65, ratio unknown) as a whitesolid. m/z: ES+ [M+H]+ 430.

This material was resolved by preparative HPLC (Chiralpak® IA-3 column,5 m silica, 20 mm diameter, 250 mm length), using an isocratic mixtureof 30% isopropanol in hexane (containing 0.1% diethylamine) as eluentsover 23 min at a flow rate of 20 mL/min. Product fractions wereconcentrated under reduced pressure to afford faster eluting isomer 1(14.3 min) of(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.045 g, 38%, Example 64) as a white solid and slower eluting isomer 2(18.8 min) of(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.045 g, 38%, Example 65) as a white solid.

Example 64, Isomer 1

¹H NMR (400 MHz, DMSO-d₆, 21° C.) 1.00-1.14 (4H, m), 1.19-1.36 (3H, m),1.69-1.84 (7H, m), 1.85-2.10 (3H, m), 2.37-2.49 (1H, m), 2.56-2.66 (1H,m), 2.79-2.90 (1H, m), 3.49-3.63 (1H, m), 4.01-4.13 (1H, m), 4.19-4.30(1H, m), 7.75 (1H, s), 7.79 (1H, d), 8.12 (1H, s), 8.39 (1H, s), 10.61(1H, s). m/z: ES+ [M+H]+ 430.

Example 65, Isomer 2

¹H NMR (400 MHz, DMSO-d₆, 21° C.) 1.01-1.14 (4H, m), 1.21-1.35 (3H, m),1.70-1.83 (7H, m), 1.83-2.09 (3H, m), 2.37-2.49 (1H, m), 2.56-2.63 (1H,m), 2.79-2.89 (1H, m), 3.49-3.62 (1H, m), 4.01-4.14 (1H, m), 4.19-4.30(1H, m), 7.74 (1H, s), 7.78 (1H, d), 8.12 (1H, s), 8.39 (1H, s), 10.61(1H, s). m/z: ES+ [M+H]+ 430.

Analytical Reverse Phase Chiral Conditions:

Column: Chiralpak® IA-3 column,

Column Dimensions: 3 μm, 4.6 mm diameter, 50 mm length,

Mobile Phase A: Hexane containing 0.1% diethylamine

Mobile Phase B: Isopropanol

Gradient: Isocratic 30% Mobile Phase B

Flow Rate: 1 mL/min over 7 min

Retention Time: 2.93 min, Example 64

-   -   3.67 min, Example 65        e.e. 100%, Isomer 1    -   98.7%, Isomer 2

Procedures for preparing the starting material5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridineare described below:

Preparation of 5-methylpyrazolo[1,5-a]pyridine

Palladium(II) acetate (0.114 g, 0.51 mmol) was added to5-bromopyrazolo[1,5-a]pyridine (1.00 g, 5.08 mmol),2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.765 g, 6.09 mmol),potassium carbonate (2.10 g, 15.2 mmol), 1,4-dioxane (10 mL), and water(1 mL) under nitrogen. The resulting mixture was stirred at 80° C. for 1hour. This reaction was repeated in a separate flask, and both reactionswere then combined, diluted with EtOAc (100 mL), and washed sequentiallywith water (75 mL) and saturated aqueous sodium chloride (75 mL). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 20% EtOAc in petroleum ether. Purefractions were concentrated under reduced pressure to afford5-methylpyrazolo[1,5-a]pyridine (1.1 g, 82%) as a brown oil. ¹H NMR (400MHz, DMSO-d₆, 20° C.) 2.33 (3H, s), 6.45 (1H, d), 6.71 (1H, dd), 7.44(1H, s), 7.92 (1H, d), 8.55 (1H, d). m/z: ES+ [M+H]+ 133.

Preparation of 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine

5-Methylpyrazolo[1,5-a]pyridine (500 mg, 3.78 mmol), palladium on carbon(10 wt %; 250 mg) and acetic acid (0.217 mL, 3.78 mmol) in MeOH (20 mL)were stirred under an atmosphere of hydrogen at 20 atm and 80° C. for 50h. This reaction was then repeated in a separate flask. Upon coolingboth reactions were filtered through Celite®, and the filtrates werecombined concentrated under reduced pressure to afford crude5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (1.05 g, 98%) as abrown oil. This product was used in the next step directly withoutfurther purification. ¹H NMR (400 MHz, DMSO-d₆, 20° C.) 1.06 (3H, d),1.57-1.72 (1H, m), 1.84-2.04 (2H, m), 2.24-2.36 (1H, mf), 2.81-2.93 (1H,m), 3.90-4.07 (1H, m), 4.11-4.19 (1H, m), 5.95 (1H, s), 7.33 (1H, s).

Preparation of 3-iodo-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine

NIS (1.98 g, 8.81 mmol) was added to5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (1.05 g, 7.34 mmol)in acetonitrile (2 mL). The resulting mixture was stirred at r.t. for 3h before being concentrated under reduced pressure. The resultingresidue was then diluted with EtOAc (100 mL) and washed sequentiallywith water (75 mL) and saturated aqueous sodium chloride (2×75 mL). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 30% EtOAc in petroleum ether.Product fractions were concentrated under reduced pressure to afford3-iodo-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (1.0 g, 52%)as a brown solid. ¹H NMR (400 MHz, DMSO-d₆, 20° C.) 1.08 (3H, d),1.58-1.72 (1H, m), 1.87-2.01 (2H, m), 2.07-2.22 (1H, m), 2.64-2.71 (1H,m), 3.93-4.06 (1H, m), 4.10-4.22 (1H, m), 7.47 (1H, s).

Preparation of5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine

n-BuLi in hexane (2.5 M; 0.916 mL, 2.29 mmol) was added dropwise to3-iodo-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (0.50 g, 1.91mmol), 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.532 g,2.86 mmol), and TMEDA (0.40 mL, 2.7 mmol) in THF (20 mL) at −78° C.under nitrogen. The resulting mixture was stirred at −78° C. for 1 hour.The reaction mixture was quenched with saturated aqueous ammoniumchloride (5 mL) and extracted with EtOAc (3×20 mL). The combined organiclayers were washed with saturated aqueous sodium chloride (50 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure to afford5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(0.60 g, 79%) contaminated with ˜23 mol %5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine based on NMR analysisas a yellow gum. m/z: ES+ [M+CH₃CN+H]+ 304.

Example 66:(1S,3R)-3-acetamido-N-(5-chloro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Acetic anhydride (0.13 mL, 1.4 mmol) was added to a stirred solution of(1S,3R)-3-amino-N-(5-chloro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(450 mg, 1.16 mmol), triethylamine (0.34 mL, 2.4 mmol) and DCM (10 mL).The reaction mixture was stirred at r.t. for 4 h. Silica was added, andthe mixture was concentrated under reduced pressure. The resultingresidue was purified by flash silica chromatography, eluting with 0.5%methanol in ethyl acetate, to give(1S,3R)-3-acetamido-N-(5-chloro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(260 mg, 52%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.)1.05-1.12 (1H, m), 1.17-1.37 (3H, m), 1.57-1.66 (2H, m), 1.69-1.95 (11H,m), 2.56-2.65 (1H, m), 2.70-2.77 (2H, m), 3.50-3.61 (1H, m), 4.21-4.45(2H, m), 7.48 (1H, s), 7.73 (1H, d), 8.05 (1H, s), 8.40 (1H, s), 10.58(1H, s). m/z: ES+ [M+H]+ 430.

Procedures for preparing the starting material(1S,3R)-3-amino-N-(5-chloro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of ethyl 1-(5-methoxy-5-oxopentyl)-1H-pyrazole-5-carboxylate

Ethyl 1H-pyrazole-5-carboxylate (9.9 g, 71 mmol) and potassium carbonate(12 g, 85 mmol) were stirred in DMF (70 mL), and methyl5-bromopentanoate (14 g, 71 mmol) was added. The mixture was stirred atambient temperature for 24 h. Water was added and the mixture wasextracted with ether (3×). The combined organic layers were combined andwashed with water (2×), dried over magnesium sulfate, and concentratedunder reduced pressure. The resulting residue was purified by flashsilica chromatography, eluting with 20% ethyl acetate in pentane to giveethyl 1-(5-methoxy-5-oxopentyl)-1H-pyrazole-5-carboxylate (9 g, 50.1%).¹H NMR (400 MHz, CDCl₃, 30° C.) 1.38 (3H, t), 1.54-1.75 (2H, m),1.8-1.95 (2H, m), 2.34 (2H, t), 3.65 (3H, s), 4.34 (2H, q), 4.58 (2H,t), 6.83 (1H, d), 7.46 (1H, d). m/z: ES+ [M+H]+ 255. Also isolated wasethyl 1-(5-methoxy-5-oxopentyl)-1H-pyrazole-3-carboxylate (7.70 g, 43%).

Preparation of methyl4-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine-5-carboxylate

Potassium tert-butoxide (6.29 g, 56.0 mmol) was added to ethyl1-(5-methoxy-5-oxopentyl)-1H-pyrazole-5-carboxylate (9.5 g, 37 mmol) intoluene (200 mL). The mixture was stirred for 10 minutes then warmed to110° C., resulting in a thick precipitate. The mixture was heated for 30minutes and then allowed to cool to r.t. The mixture was neutralized topH 7 with dilute aqueous HCl (2N) and extracted with ethyl acetate (3×).The combined organic layers were dried over magnesium sulfate andconcentrated under reduced pressure to afford methyl4-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine-5-carboxylate (8.00g, 103%) contaminated with the ethyl ester analog This material was useddirectly in the next step without further purification. m/z: ES+ [M+H]+209 (Me ester) & 223 (Et ester).

Preparation of 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-4-one

Lithium chloride (2.60 g, 61.2 mmol) was added to a solution of methyl4-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine-5-carboxylate (8.50g, 40.8 mmol, contaminated with the ethyl ester analog) in DMSO (50 mL).The mixture was heated at 120° C. for 24 h and then cooled to r.t. Waterwas added, and the mixture was extracted with ethyl acetate (3×). Thecombined organic layers were concentrated under reduced pressure. Theresulting residue was purified by flash silica chromatography, elutingwith 30% ethyl acetate in heptane to give5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-4-one (3.50 g, 57%) as anoil. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.91-2.08 (2H, m), 2.08-2.28 (2H,m), 2.76-2.93 (2H, m), 4.49-4.64 (2H, m), 6.86 (1H, d), 7.44 (1H, d).

Preparation 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine

Hydrazine hydrate (5.65 mL, 117 mmol) was added to a stirred solution of5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-4-one (3.5 g, 23 mmol)dissolved in diethylene glycol (66 mL). The resulting solution wasstirred at 170° C. for 1 hour. The reaction was then removed from heat,and potassium hydroxide (4.58 g, 81.6 mmol) was carefully added to themixture. The resulting suspension was stirred at 170° C. for 2 h andthen cooled to r.t. The reaction mixture was then diluted water,acidified to pH 5 with dilute aqueous hydrochloric acid (2N), andextracted with Et₂O (5×50 mL). The combined ether layers were washedwith water (2×20 mL), dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to give5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine (2.10 g, 66%) as a solid.¹H NMR (400 MHz, CDCl₃, 30° C.) 1.61-1.67 (2H, m), 1.71-1.79 (2H, m),1.80-1.87 (2H, m), 2.62-2.83 (2H, m), 4.17-4.3 (2H, m), 5.98 (1H, d),7.26 (1H, d).

Preparation of 3-iodo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine

NIS (3.47 g, 15.4 mmol) was added to a stirred solution of5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine (2.10 g, 15.4 mmol)dissolved in acetonitrile (30 mL) at r.t. The resulting mixture wasstirred at r.t. for 16 h. The reaction mixture was then diluted withether (50 mL), and washed sequentially with water (2×20 mL) andsaturated aqueous sodium chloride (20 mL). The organic layer was driedover MgSO₄, filtered, and concentrated under reduced pressure to afford3-iodo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine (3.3 g, 82%) as anorange oil which solidified on standing. This material was used directlyin the next step without further purification. ¹H NMR (400 MHz, CDCl₃,30° C.) 1.6-1.72 (2H, m), 1.73-1.82 (2H, m), 1.82-1.92 (2H, m),2.74-2.83 (2H, m), 4.25-4.35 (2H, m), 7.32 (1H, s).

Preparation of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine

Isopropylmagnesium chloride lithium chloride complex in THF (1.3 M; 12.6mL, 16.4 mmol) was added dropwise over 5 minutes to3-iodo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine (3.30 g, 12.6 mmol)in THF (20 mL) at 0° C. under nitrogen. The resulting mixture wasstirred at 0° C. for 30 minutes.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.85 mL, 18.9mmol) was added dropwise at 0° C., and the reaction mixture was thenallowed to warm to r.t. overnight. The reaction mixture was diluted withether (20 mL) and washed sequentially with saturated aqueous ammoniumchloride (20 mL), water (20 mL), and saturated aqueous sodium chloride(10 mL). The organic layer was dried over MgSO₄, filtered, andconcentrated under reduced pressure. The resulting oil was taken up inheptane, resulting in formation of a white mixture. This mixture wasfiltered to afford3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine(2.00 g, 61%) as a white solid. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.29(12H, s), 1.63-1.72 (2H, m), 1.72-1.8 (2H, m), 1.80-1.87 (2H, m),2.88-3.09 (2H, m), 4.20-4.33 (2H, m), 7.56 (1H, s).

Preparation of tert-butyl((1R,3S)-3-((5-chloro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate

2nd Generation XPhos Precatalyst (0.16 g, 0.21 mmol) was added to adegassed mixture of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine(0.656 g, 2.50 mmol), tert-butyl(1R,3S)-3-((5-chloro-4-iodopyridin-2-ylcarbamoyl)cyclohexyl)carbamate(1.00 g, 2.08 mmol; prepared according to Example 10) and potassiumphosphate, tribasic, (1.09 g, 6.25 mmol) in 1,4-dioxane (20 mL) andwater (2 mL). The mixture was again degassed and was stirred at 85° C.for 24 h under nitrogen. The reaction mixture was allowed to cool, andsilica was added. This new mixture was concentrated under reducedpressure, and the resulting residue was purified by flash silicachromatography, eluting with 50% ethyl acetate in heptane to givetert-butyl((1R,3S)-3-((5-chloro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.70 g, 69%) as a solid. This material was carried on to the next stepwithout further purification. m/z: ES+ [M+H]+ 488.

Preparation of(1S,3R)-3-amino-N-(5-chloro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

TFA (2 mL) was added to a stirred solution of tert-butyl((1R,3S)-3-((5-chloro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(700 mg, 1.43 mmol) in DCM (10 mL). The reaction was stirred at r.t. for24 h, the volatiles removed under vacuum, and the resulting residue waspurified by ion exchange chromatography using an SCX column, elutingwith 7N ammonia in methanol. Product fractions were concentrated underreduced pressure to afford(1S,3R)-3-amino-N-(5-chloro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(550 mg, 99%) as a solid. m/z: ES+ [M+H]+ 388.

Example 67:N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide

HATU (166 mg, 0.44 mmol) and DIPEA (0.18 mL, 1.0 mmol) were addedsequentially to a solution of(1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamidedihydrochloride (150 mg, 0.34 mmol; prepared according to Example 31b)and oxetane-3-carboxylic acid (45 mg, 0.44 mmol) in DMF (1.2 mL). Thereaction was stirred at r.t. for 3 h before being diluted with saturatedaqueous sodium hydrogencarbonate and extracted with EtOAc (3×). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting crude gum waspurified by preparative HPLC (Waters XBridge Prep Phenyl OBD column, 5μsilica, 19 mm diameter, 150 mm length) using decreasingly polar mixturesof water (containing 0.2% ammonium hydroxide, pH 10) and MeCN as eluentsto affordN-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)-oxetane-3-carboxamide(20 mg).

A second reaction was set up as follows: HATU (140 mg, 0.37 mmol) wasadded to a solution of(1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamidedihydrochloride (150 mg, 0.34 mmol), oxetane-3-carboxylic acid (45 mg,0.44 mmol), DIPEA (0.18 mL, 1.0 mmol) and DMF (1.2 mL). The reaction wasstirred at r.t. for 3 h. The reaction was diluted with EtOAc and washedwith saturated NaHCO₃ and saturated aqueous sodium chloride. The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. The resulting residue was purified by flash silicachromatography, eluting with gradient 80 to 100% EtOAc in hexane, toaffordN-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide(50 mg) as a white solid. This residue was combined with the productfrom the first reaction and repurified by preparative HPLC (WatersXBridge Prep Phenyl OBD column, 5a silica, 19 mm diameter, 150 mmlength) to affordN-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide(54 mg, 17%) as a white solid. ¹H NMR (300 MHz, CDCl₃, 27° C.) 1.10-1.26(1H, m), 1.37-1.68 (3H, m), 2.17-1.84 (7H, m), 2.37-2.22 (1H, m),2.57-2.43 (1H, m), 2.95 (2H, t), 3.67 (1H, tt), 3.85-4.00 (1H, m), 4.24(2H, t), 4.89-4.78 (4H, m), 5.52 (1H, br d), 7.93 (1H, s), 8.27 (1H, s),8.28 (1H, s), 8.60 (1H, br s). m/z: ES+ [M+H]+ 458.

Examples 68 and 69: Isomer 1 and Isomer 2 of(1S,3R)-3-acetamido-N-(5-chloro-4-(6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Pure Enantiomers

The configuration of the methyl is unknown for Example 68 and 69 but isopposite in Example 68 vs 69.

(1S,3R)-3-Acetamido-N-(5-chloro-4-(6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(163 g, 0.379 mmol; mixture of Examples 68 and 69, unknown ratio) wasseparated using SFC conditions (Column: Chiralpak AS, 5 am, 21.2 mmdiameter, 250 mm length, 20 mL/min flow rate over 7 min), eluting with25% methanol in C02, to afford Isomer 1 (3.10 min) of(1S,3R)-3-acetamido-N-(5-chloro-4-(6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(65 mg, 28%, Example 68) and Isomer 2 (4.09 min) of(1S,3R)-3-acetamido-N-(5-chloro-4-(6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(68, 29%, Example 69) as white solids.

Example 68, Isomer 1

¹H NMR (300 MHz, CDCl₃, 27° C.) 1.05-1.25 (4H, m), 1.65-1.33 (4H, m),1.85-2.09 (7H, m), 2.15-2.32 (2H, m), 2.38-2.53 (1H, m), 2.86-3.03 (2H,m), 3.70 (1H, dd), 3.82-3.97 (1H, m), 4.33 (1H, dd), 5.47 (1H, br d),7.89 (1H, s), 8.12 (1H, br s), 8.22 (1H, s), 8.27 (1H, s). m/z: ES+[M+H]+ 430.

Example 69, Isomer 2

¹H NMR (300 MHz, CDCl₃, 27° C.) 1.09-1.24 (4H, d), 1.34-1.58 (4H, m),1.86-2.08 (7H, m), 2.15-2.32 (1H, m), 2.41-2.51 (1H, m), 2.86-3.03 (1H,m), 3.64-3.75 (1H, m), 3.81-3.95 (1H, m), 4.33 (1H, dd), 5.52 (1H, brd), 7.88 (1H, s), 8.15-8.21 (2H, m), 8.27 (1H, s). m/z: ES+ [M+H]+ 430.

Analytical SFC Conditions:

Column: Chiralpak AS

Column Dimensions: 5 μm, 4.6 mm diameter, 50 mm length,

Mobile Phase A: C02 (100%)

Mobile Phase B: Methanol

Gradient: Isocratic 25% Mobile Phase B

Flow Rate: 1 mL/min over 2 min

Retention Time: 1.05 min, Example 68, Isomer 1

-   -   1.44 min, Example 69, Isomer 2        e.e. >98%, Example 68, Isomer 1    -   >98%, Example 69, Isomer 2

Procedures used to prepare the starting material(1S,3R)-3-acetamido-N-(5-chloro-4-(6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of 6-methylpyrazolo[1,5-a]pyridine

Dioxane (32 mL) and water (6.0 mL) were added to potassium carbonate(1.82 g, 13.2 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (1.9mL, 13 mmol) and 6-bromopyrazolo[1,5-a]pyridine (1.3 g, 6.60 mmol). Thereaction suspension was degassed with nitrogen. 3rd Generation RuPhosPrecatalyst (0.27 g, 0.33 mmol) was added, and the reaction was immersedin an oil bath that had been preheated to 100° C. The reaction wasmaintained under these conditions for 4 h and then cooled to r.t. Theresulting mixture was filtered, and the filtrate was washed withsaturated aqueous sodium chloride. The organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresulting oil was purified by flash silica chromatography, elutiongradient 5 to 40% ethyl acetate in hexane to give6-methylpyrazolo[1,5-a]pyridine (0.680 g, 78%) as a white solid. ¹H NMR(300 MHz, CDCl₃, 27° C.) 2.29 (3H, s), 6.53 (1H, dd), 7.07 (1H, dd),7.60 (1H, d), 7.90 (1H, d), 8.49-8.52 (1H, m). m/z: ES+ [M+H]+ 133.

Preparation of 6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine

Methanol (45 mL) and acetic acid (0.5 mL) were added to a flask chargedwith 6-methylpyrazolo[1,5-a]pyridine (0.71 g, 5.4 mmol) and platinum(IV)oxide (0.12 g, 0.54 mmol). The flask was purged with nitrogen,evacuated, and then subjected to a hydrogen atmosphere (balloon). Thereaction was stirred at 35° C. for 18 h and then filtered through a bedof Celite®. The filtrate was concentrated under reduced pressure andthen diluted with diethyl ether. The mixture was washed with saturatedaqueous sodium hydrogencarbonate and saturated aqueous sodium chloride.The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure to give crude6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (0.71 g, 97%) as anoff-white solid. ¹H NMR (300 MHz, CDCl₃, 27° C.) 1.1 (3H, d), 1.50 (1H,dtd), 1.92-2.01 (1H, m), 2.08-2.27 (1H, m), 2.64-2.80 (1H, m), 2.87-2.96(1H, m), 3.64 (1H, dd), 4.27 (1H, ddd), 5.99 (1H, s), 7.39 (1H, d). m/z:ES+ [M+H]+ 137.

Preparation of 3-iodo-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine

NIS (1.16 g, 5.14 mmol) was added to a solution of6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (0.70 g, 5.14 mmol)in acetonitrile (12 mL) at r.t. The reaction was stirred under theseconditions for 18 h and then diluted with EtOAc. The resulting mixturewas washed with water, and the aqueous layer was extracted with EtOAc(4×100 mL). The combined organic layers were washed with saturatedaqueous sodium chloride and concentrated under reduced pressure. Theresulting crude gum was purified by flash silica chromatography, elutiongradient 5 to 50% ethyl acetate in hexanes, to give3-iodo-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (1.10 g, 82%)as a white solid. ¹H NMR (300 MHz, CDCl₃, 27° C.) 1.15 (3H, d),1.42-1.61 (1H, m), 1.90-2.07 (1H, m), 2.08-2.22 (1H, m), 2.52-2.60 (1H,m), 2.75-2.86 (1H, m), 3.65 (1H, dd), 4.26 (1H, dd), 7.49 (1H, s). m/z:ES+ [M+H]+ 263.

Preparation of6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine

Tetrahydrofuran (3 mL) was added to a flask charged with3-iodo-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (0.40 g, 1.53mmol). The reaction was immersed in an ice-bath, and isopropylmagnesiumchloride lithium chloride complex in THF (1.3 M; 1.5 mL, 2.0 mmol) wasadded dropwise. The reaction was maintained between 0 and 3° C. for 30min. Then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.426 g,2.29 mmol) was added via syringe, and the ice bath was removed. Thereaction was maintained under these conditions for 18 h and then dilutedwith saturated aqueous ammonium chloride. The mixture was extracted inEtOAc (3×), and the combined organic layers were dried over sodiumsulfate, filtered and concentrated under reduced pressure to afford6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(0.186 g). This material was used in the next step without furtherpurification. m/z: ES+ [M+H]+ 263.

Preparation of(1S,3R)-3-acetamido-N-(5-chloro-4-(6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Mixture of Examples 68 and 69, Ratio Unknown

1,4-Dioxane (5 mL) and water (0.63 mL) were added to a flask chargedwith(1S,3R)-3-acetamido-N-(5-chloro-4-iodopyridin-2-yl)cyclohexanecarboxamide(0.23 g, 0.55 mmol; prepared according to Example 12) and6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(0.19 g, 0.71 mmol). The reaction mixture was evacuated and purged withnitrogen. Then cesium carbonate (0.444 g, 1.36 mmol) and PdCl₂(dppf)(0.040 g, 0.05 mmol) were added. The reaction was set in an oil bathpreheated to 95° C., and the reaction was maintained under theseconditions for 2 h. The reaction was then cooled to r.t. and filteredthrough Celite® using an ethyl acetate wash. The filtrate was washedwith saturated aqueous sodium chloride, and the organic layer was driedover sodium sulfate, filtered and concentrated under reduced pressure.The resulting gray solid was purified by flash silica chromatography,elution gradient 1 to 10% methanol in ethyl acetate, to afford(1S,3R)-3-acetamido-N-(5-chloro-4-(6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.16 g, 69%). ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 0.99-1.15 (4H, m),1.20-1.33 (3H, m), 1.37-1.48 (1H, m), 1.68-1.77 (6H, m), 1.81-1.92 (2H,m), 2.10-2.20 (1H, m), 2.54-2.62 (1H, m), 2.79-2.87 (2H, m), 3.48-3.61(1H, m), 3.65 (1H, dd), 4.26 (1H, dd), 7.73 (1H, br d), 7.76 (1H, s),8.15 (1H, s), 8.38 (1H, s), 10.58 (1H, s). m/z: ES+ [M+H]+ 430.

Example 70 and Example 71: Preparation of isomer 1 and isomer 2 of(1S,3R)-3-acetamido-N-(5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Pure Enantiomers

The configuration of the methoxy is unknown for Examples 70 and 71 butis opposite in Example 70 vs Example 71.

(1S,3R)-3-acetamido-N-(5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(100 mg, 0.22 mmol) was resolved by preparative HPLC conditions(Chiralpak IA column, 5 μm, 20 mm diameter, 250 mm length, 25° C. columntemperature, 15 mL/min flow rate), eluting with isocratic 50% ethanol inhexane over 22 min to afford faster eluting (10.8 min) isomer 1 of(1S,3R)-3-acetamido-N-(5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.030 g, 30%) and slower eluting (17.9 min) isomer 2 of(1S,3R)-3-acetamido-N-(5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.030 g, 30%) as white solids.

Example 70, Isomer 1

¹H NMR (400 MHz, DMSO-d₆, 19° C.) 1.00-1.14 (1H, m), 1.20-1.34 (3H, m),1.72-1.80 (6H, m), 1.84-1.97 (2H, m), 2.07-2.19 (1H, m), 2.56-2.66 (1H,m), 2.70-2.92 (2H, m), 3.36 (3H, s), 3.48-3.63 (1H, m), 3.93-4.02 (1H,m), 4.23 (2H, d), 7.76-7.83 (2H, m), 8.15 (1H, s), 8.39 (1H, s), 10.64(1H, s). m/z: ES+ [M+H]+ 446.

Example 71, Isomer 2

¹H NMR (400 MHz, DMSO-d₆, 19° C.) 1.00-1.17 (1H, m), 1.19-1.35 (3H, m),1.72-1.80 (6H, m), 1.85-1.97 (2H, m), 2.06-2.19 (1H, m), 2.55-2.63 (1H,m), 2.71-2.92 (2H, m), 3.36 (3H, s), 3.50-3.62 (1H, m), 3.93-4.02 (1H,m), 4.23 (2H, d), 7.76-7.83 (2H, m), 8.16 (1H, s), 8.39 (1H, s), 10.64(1H, s). m/z: ES+ [M+H]+ 446.

Analytical SFC Conditions:

Column: Chiralpak IA-3 column,

Column Dimensions: 3 μm, 4.6 mm diameter, 50 mm length,

Column Temperature: 25° C.

Mobile Phase A: Hexane containing 0.1% diethylamine

Mobile Phase B: Ethanol

Gradient: Isocratic 50% Mobile Phase B

Flow Rate: 1.5 mL/min over 10 min

Retention Time: 1.31 min, Example 70, Isomer 1

-   -   2.04 min, Example 71, Isomer 2        e.e. 100%, Example 70, Isomer 1    -   100%, Example 71, Isomer 2

Procedures used to prepare the starting material(1S,3R)-3-acetamido-N-(5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of 6-methoxypyrazolo[1,5-a]pyridine

Cesium carbonate (3.31 g, 10.2 mmol) was added to6-bromopyrazolo[1,5-a]pyridine (1.00 g, 5.08 mmol), MeOH (0.41 mL, 10mmol), palladium acetate (0.057 g, 0.25 mmol) and2-(di-1-adamantylphosphino)-3,6-dimethoxy-2′,4′6′-triisopropyl-1,1′-biphenyl(AdBrettPhos; 0.14 g, 0.25 mmol) in toluene (10 mL). The resultingmixture was stirred at 90° C. for 2 h. The above reaction was repeatedin a separate reaction. Once both reactions were cooled, they werecombined, filtered, and concentrated under reduced pressure. Theresulting residue was purified by flash silica chromatography, elutiongradient 0 to 20% EtOAc in petroleum ether. Pure fractions wereconcentrated under reduced pressure to afford6-methoxypyrazolo[1,5-a]pyridine (0.83 g, 55%) as a colourless oil. ¹HNMR (400 MHz, DMSO-d₆, 27° C.) 3.82 (3H, s), 6.54 (1H, s), 7.01 (1H, d),7.61 (1H, d), 7.87 (1H, s), 8.38 (1H, s).

Preparation of 6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine

6-Methoxypyrazolo[1,5-a]pyridine (0.36 g, 2.4 mmol) and palladium oncarbon (10 wt %; 0.078 g, 0.73 mmol) in MeOH (50 mL) was stirred underan atmosphere of hydrogen at 20 atm and 80° C. for 16 h. The mixture wasfiltered through a Celite® pad, and the filtrate was concentrated underreduced pressure. The resulting residue was diluted with EtOAc (25 mL)and washed sequentially with saturated saturated aqueous sodiumhydrogencarbonate (25 mL) and saturated aqueous sodium chloride (25 mL).The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (0.30 g, 81%) as ayellow waxy solid. ¹H NMR (400 MHz, DMSO, 20° C.) 1.85-1.94 (1H, m),1.98-2.09 (1H, m), 2.71-2.78 (2H, m), 3.32 (3H, s), 3.89 (1H, m),4.02-4.18 (2H, m), 5.97 (1H, d), 7.34 (1H, d).

Preparation of3-iodo-5-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine

NIS (0.559 g, 2.48 mmol) was added to5-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (0.27 g, 1.77 mmol)in acetonitrile (10 mL). The resulting mixture was stirred at r.t. for30 minutes. The reaction mixture was concentrated under reducedpressure, and the resulting residue was diluted with EtOAc (25 mL). Thisnew mixture was washed sequentially with water (25 mL) and saturatedaqueous sodium chloride (25 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue was purified by flash silica chromatography, elution gradient 0to 30% EtOAc in petroleum ether. Product fractions were concentratedunder reduced pressure to afford3-iodo-5-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (0.40 g, 81%)as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆, 21° C.) 1.78-1.99 (1H, m),2.02-2.23 (1H, m), 2.53-2.60 (2H, m), 3.34 (3H, s), 3.82-3.96 (1H, m),4.07-4.26 (2H, m), 7.48 (1H, s).

Preparation of6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine

n-BuLi (0.805 mL, 2.01 mmol) was added to3-iodo-6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (0.4 g, 1.44mmol), 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.401 g,2.16 mmol), and TMEDA (0.30 mL, 2.0 mmol) in THF (20 mL) cooled to −78°C. under nitrogen. The resulting mixture was maintained at −78° C. for 1hour. The reaction mixture was then quenched with saturated aqueousammonium chloride (200 mL), extracted with EtOAc (3×150 mL), the organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure to afford6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(0.400 g, 100%) as a colourless gum, contaminated with 14 wt % des-iodostarting material (NMR analysis). This material was carried on to thenext step without further purification.

Preparation of tert-butyl((1R,3S)-3-((5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate

2nd Generation XPhos Precatalyst (0.049 g, 0.06 mmol) was added to6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(0.387 g, 1.25 mmol), tert-butyl((1R,3S)-3-((5-chloro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.3 g, 0.63 mmol; prepared according to Example 10) and cesiumcarbonate (0.611 g, 1.88 mmol) in dioxane (10 mL) and water (1 mL) undernitrogen. The resulting mixture was stirred at 100° C. for 1 hour, andthe reaction mixture was then cooled and diluted with EtOAc (200 mL).The resulting mixture was washed sequentially with water (200 mL) andsaturated aqueous sodium chloride (200 mL). The organic layer was driedover sodium sulfate, filtered and concentrated under reduced pressure.The resulting residue was purified by flash silica chromatography,elution gradient 0 to 60% EtOAc in petroleum ether. Pure fractions wereconcentrated under reduced pressure to afford tert-butyl((1R,3S)-3-((5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.14 g, 44%) as a white solid. m/z: ES+ [M+H]+ 504.

Preparation of(1S,3R)-3-amino-N-(5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

TFA (4 mL, 51.92 mmol) was added to tert-butyl((1R,3S)-3-((5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.14 g, 0.28 mmol) in DCM (10 mL). The resulting mixture was stirred atr.t. for 1 hour. The reaction was concentrated under reduced pressure toafford crude(1S,3R)-3-amino-N-(5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamideas the di-trifluoroacetic acid salt (0.15 g, 98%) and a yellow gum. m/z:ES+ [M+H]+ 404.

Preparation of(1S,3R)-3-acetamido-N-(5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Mixture of Examples 70 and 71, Ratio Unknown

Acetic anhydride (0.023 mL, 0.25 mmol) was added to(1S,3R)-3-amino-N-(5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(di-trifluoroacetic acid salt; 0.15 g, 0.25 mmol) and TEA (0.17 mL, 1.2mmol) in DCM (5 mL). The resulting mixture was stirred at r.t. for 16 h.The reaction was then concentrated under reduced pressure, and the crudeproduct was purified by preparative HPLC (XBridge Prep C18 OBD column,21.2 mm diameter, 250 mm length), using decreasingly polar mixtures ofwater (containing 0.1% NH₄HCO₃) and MeCN as eluents. Fractionscontaining the desired compound were concentrated under reduced pressureto afford(1S,3R)-3-acetamido-N-(5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.100 g, 91%; mixture of Examples 70 and 71) as a white solid. m/z: ES+[M+H]+ 446.

Example 72 and Example 73: Preparation of isomer 1 and isomer 2 of(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Pure Enantiomers

The configuration of the methoxy is unknown for Examples 72 and 73 butis opposite in Example 72 vs Example 73

(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(120 mg, 0.270 mmol; prepared according to the procedures of Examples 70and 71 substituting 5-bromopyrazolo[1,5-a]pyridine for6-bromopyrazolo[1,5-a]pyridine) was resolved by preparative HPLCconditions (Chiralpak ID column, 5 m, 20 mm diameter, 250 mm length, 25°C. column temperature, 15 mL/min flow rate), eluting with isocratic 50%ethanol in hexane over 31 min to afford faster eluting (16.0 min) isomer1 of(1S,3R)-3-acetamido-N-(5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.040 g, 33.3%) and slower eluting (24.8 min) isomer 2 of(1S,3R)-3-acetamido-N-(5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(0.040 g, 33.3%) as white solids.

Example 72, Isomer 1

¹H NMR (400 MHz, DMSO-d₆, 19° C.) δ 1.03-1.14 (1H, m), 1.19-1.35 (3H,m), 1.65-1.84 (6H, m), 1.84-1.94 (1H, m), 2.16-2.25 (2H, m), 2.56-2.66(1H, m), 2.83-2.94 (1H, m), 2.97-3.08 (1H, m), 3.29 (3H, s), 3.50-3.63(1H, m), 3.82-3.91 (1H, m), 4.06-4.24 (2H, m), 7.77 (1H, s), 7.80 (1H,d), 8.13 (1H, s), 8.39 (1H, s), 10.64 (1H, s). m/z: ES+ [M+H]+ 446.

Example 73, Isomer 2

¹H NMR (400 MHz, DMSO-d₆, 19° C.) δ 1.00-1.14 (1H, m), 1.19-1.35 (3H,m), 1.72-1.81 (6H, m), 1.84-1.92 (1H, m), 2.16-2.25 (2H, m), 2.56-2.66(1H, m), 2.83-2.93 (1H, m), 3.03 (1H, m), 3.29 (3H, s), 3.48-3.62 (1H,m), 3.82-3.91 (1H, m), 4.06-4.24 (2H, m), 7.77 (1H, s), 7.80 (1H, d),8.13 (1H, s), 8.39 (1H, s), 10.64 (1H, s). m/z: ES+ [M+H]+ 446.

Analytical SFC Conditions:

Column: Chiralpak ID-3 column,

Column Dimensions: 3 μm, 4.6 mm diameter, 50 mm length,

Column Temperature: 25° C.

Mobile Phase A: Hexane containing 0.1% diethylamine

Mobile Phase B: Ethanol

Gradient: Isocratic 50% Mobile Phase B

Flow Rate: 1.5 mL/min over 10 min

Retention Time: 1.57 min, Example 72, Isomer 1

-   -   2.54 min, Example 73, Isomer 2        e.e. 99.9%, Example 72, Isomer 1    -   >99%, Example 73, Isomer 2

Example 74: Preparation of(1S,3R)-3-acetamido-N-(5-fluoro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Acetic anhydride (0.11 mL, 1.1 mmol) was added to a stirred solution of(1S,3R)-3-amino-N-(5-fluoro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(350 mg, 0.94 mmol), triethylamine (0.28 mL, 2.0 mmol) and DCM (10 mL).The reaction mixture was stirred at r.t. for 4 h. Silica was added, andthe resulting mixture was concentrated under reduced pressure. Theresulting adsorbed residue was purified by flash silica chromatography,eluting with 0.5% methanol in ethyl acetate, to afford(1S,3R)-3-acetamido-N-(5-fluoro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(200 mg, 51%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.)1.03-1.07 (1H, m), 1.30 (3H, m), 1.57-1.96 (13H, m), 2.56-2.62 (1H, m),2.68-2.93 (2H, m), 3.47-3.66 (1H, m), 4.19-4.4 (2H, m), 7.49 (1H, d),7.73 (1H, d), 8.09 (1H, d), 8.32 (1H, d), 10.48 (1H, s). m/z: ES+ [M+H]+414.

Procedures used to prepare the starting material(1S,3R)-3-amino-N-(5-fluoro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of3-(2-chloro-5-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine

2-Chloro-5-fluoro-4-iodopyridine (1.064 g, 4.13 mmol).3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine(1.30 g, 4.96 mmol; prepared according to Example 66), 2nd GenerationXPhos Precatalyst (0.325 g, 0.41 mmol) and potassium phosphate, dibasic,(2.16 g, 12.4 mmol) were dissolved in degassed dioxane (20 mL) and water(1 mL) at 21° C. The mixture was stirred at 90° C. for 24 h and thencooled. The mixture was diluted with EtOAc (30 mL), washed with water(10 mL), and then concentrated under reduced pressure. The resultingresidue was purified by flash silica chromatography, elution gradient 0to 50% EtOAc in heptane. Product fractions were evaporated to dryness toafford3-(2-chloro-5-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine(0.650 g, 59%) as an oil. ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.62-1.94 (6H,m), 2.77-2.88 (2H, m), 4.29-4.4 (2H, m), 7.22 (1H, d), 7.50 (1H, d),8.25 (1H, d). m/z: ES+ [M+H]+ 266.

Preparation of tert-butyl((1R,3S)-3-((5-fluoro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate

Tetrakis(triphenylphosphine)palladium(0) (0.30 g, 0.26 mmol) was addedto a degassed mixture of3-(2-chloro-5-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine(0.700 g, 2.63 mmol), tert-butyl((1R,3S)-3-carbamoylcyclohexyl)carbamate (0.638 g, 2.63 mmol; preparedaccording to Example 25),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.305 g, 0.53 mmol) andcesium carbonate (2.58 g, 7.90 mmol) in 1,4-dioxane (10 mL). Theresulting mixture was purged for 5 mins under nitrogen, and theresulting suspension was subjected to microwave conditions (120° C., 17h). The reaction mixture was cooled and partitioned between water (20mL) and ethyl acetate (100 mL) before being filtered. The layers wereseparated, and the organic layer concentrated under reduced pressure,adsorbed onto silica, and purified by flash silica chromatography,eluting with 50% EtOAc in heptane. Product fractions were concentratedunder reduced pressure to afford crude tert-butyl((1R,3S)-3-((5-fluoro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.90 g, 72%) as a white solid. m/z: ES+ [M+H]+ 472.

Preparation of(1S,3R)-3-amino-N-(5-fluoro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

TFA (1 mL) was added to a solution of tert-butyl((1R,3S)-3-((5-fluoro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(600 mg, 1.27 mmol) in DCM (10 mL). The mixture was stirred at r.t. for24 h, and then the reaction was concentrated under reduced pressure. Theresulting residue was purified by ion-exchange chromatography, using anSCX column and eluting with 7N ammonia in methanol. Product fractionswere concentrated under reduced pressure to afford(1S,3R)-3-amino-N-(5-fluoro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(350 mg, 74%) as a white solid. m/z: ES+ [M+H]+ 372.

Example 75: Preparation of(1S,3R)—N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-methylpyridin-2-yl)-3-(2-hydroxvacetamido)cyclohexanecarboxamide

Cesium carbonate (436 mg, 1.34 mmol) and 2nd Generation XPhosPrecatalyst (35 mg, 0.04 mmol) were added to a degassed mixture of5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(168 mg, 0.470 mmol; prepared according to Example 23) and(1S,3R)-3-(2-hydroxyacetamido)-N-(4-iodo-5-methylpyridin-2-yl)cyclohexanecarboxamide(186 mg, 0.45 mmol) in 1,4-dioxane (3.7 mL) and water (0.7 mL) to give acolorless solution. The reaction was stirred at 85° C. for 18 h and thencooled and diluted with EtOAc (50 mL). This new mixture was washed withwater and saturated aqueous sodium chloride. The aqueous layers wereextracted with EtOAc (2×50 mL). The combined organic layers were driedover magnesium sulfate, filtered, and concentrated under reducedpressure. The resulting residue was adsorbed onto silica gel andpurified by flash silica chromatography, eluting with 10% MeOH in DCM,to afford(1S,3R)—N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-methylpyridin-2-yl)-3-(2-hydroxyacetamido)cyclohexanecarboxamide(78 mg, 41%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.18-1.38 (9H, m), 1.46 (1H, q), 1.65-1.92 (4H, m), 2.32 (3H, s),2.57-2.67 (1H, m), 2.85 (2H, s), 3.58-3.72 (1H, m), 3.78 (1H, d), 3.93(2H, s), 5.36 (1H, t), 7.54 (1H, d), 7.77 (1H, s), 8.07 (1H, s), 8.13(1H, 2), 10.27 (1H, s). m/z: ES+ [M+H]+ 426.

Optical Rotation:

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 25° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: DMSO

[α]=+82

Procedures used to prepare the starting material(1S,3R)-3-(2-hydroxyacetamido)-N-(4-iodo-5-methylpyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of(1S,3R)-3-amino-N-(4-iodo-5-methylpyridin-2-yl)cyclohexanecarboxamide

Hydrochloric acid in dioxane (4M; 2 mL, 8 mmol) was added to tert-butyl((1R,3S)-3-((4-iodo-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)carbamate(530 mg, 1.15 mmol; prepared according to Example 47) in MeOH (11 mL) togive a colorless solution. The reaction was stirred for 2 h at r.t. andthen concentrated under reduced pressure to afford(1S,3R)-3-amino-N-(4-iodo-5-methylpyridin-2-yl)cyclohexanecarboxamide(550 mg) as the dihydrochloride salt, a white solid. This solid wascarried on to the next step without further purification. 1H NMR (300MHz, DMSO-d₆, 27° C.) 1.11-1.36 (3H, m), 1.49 (1H, q), 1.76-1.88 (2H,m), 1.88-1.89 (1H, m) 2.04 (1H, d), 2.30 (3H, s), 2.54-2.67 (1H, m),2.94-3.07 (1H, m), 8.03 (3H, br. s), 8.17 (1H, s), 8.61 (1H, s), 10.58(1H, br. s). One HCl equivalent detected, second assumed to be buriedunder broad HOD peak at 5.9 ppm. m/z: ES+ [M+H]+ 360.

Preparation of(1S,3R)-3-(2-hydroxvacetamido)-N-(4-iodo-5-methylpyridin-2-yl)cyclohexanecarboxamide

HATU (328 mg, 0.86 mmol) was added to a mixture of(1S,3R)-3-amino-N-(4-iodo-5-methylpyridin-2-yl)cyclohexanecarboxamidedihydrochloride (228 mg, 0.53 mmol), 2-hydroxyacetic acid (66 mg, 0.86mmol), TEA (0.24 mL, 1.7 mmol), DMF (2.8 mL), and DCM (2.8 mL). Thereaction was stirred at r.t. under nitrogen for 5 h and thenconcentrated under reduced pressure. The resulting residue was taken upin DCM and washed with water (4×25 mL) and saturated aqueous sodiumchloride. The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was adsorbedonto silica gel and purified by flash silica chromatography, elutingwith 0 to 10% methanol in DCM, to afford(1S,3R)-3-(2-hydroxyacetamido)-N-(4-iodo-5-methylpyridin-2-yl)cyclohexanecarboxamide(186 mg, 52%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.17-1.34 (3H, m) 1.43 (1H, q) 1.60-1.91 (4H, m) 2.28 (3H, s), 2.54-2.69(1H, m), 3.56-3.72 (1H, m), 3.78 (2H, d), 5.36 (1H, t) 7.55 (1H, d) 8.16(1H, s) 8.61 (1H, s) 10.45 (1H, s). m/z: ES+ [M+H]+ 418.

Example 76: Preparation ofN-((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide

Cesium carbonate (247 mg, 0.76 mmol) and 2nd Generation XPhosPrecatalyst (20 mg, 0.03 mmol) were added to a degassed mixture of5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(90 mg, 0.25 mmol; prepared according to Example 23) andN-((1R,3S)-3-((4-iodo-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide(112 mg, 0.25 mmol) in 1,4-dioxane (2.1 mL) and water (0.4 mL). Thereaction was stirred at 85° C. for 18 h, cooled to r.t., and thendiluted with EtOAc (50 mL). The mixture was washed with water andsaturated aqueous sodium chloride. The combined aqueous layers wereextracted with EtOAc (2×50 mL), and the combined organic layers weredried over magnesium sulfate, filtered, and concentrated under reducedpressure. The resulting residue was adsorbed onto silica gel andpurified by flash silica chromatography, eluting with 10% MeOH in DCM,to afford an off-white solid (72 mg). This material was repurified byflash silica chromatography, 0 to 10% methanol in DCM, to affordN-((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-methylpyridin-2yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide(50 mg, 44%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.00-1.17 (1H, m), 1.21-1.37 (9H, m) 1.68-1.84 (3H, m), 1.89 (1H, br d),2.33 (3H, s), 2.55-2.67 (1H, m), 2.84 (2H, s), 3.53-3.74 (2H, m), 3.93(2H, s), 4.54-4.65 (4H, m), 7.73-7.84 (2H, m), 8.07 (1H, s), 8.14 (1H,s), 10.28 (1H, s). m/z: ES+ [M+H]+ 452.

Optical Rotation:

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 25° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: DMSO

[α]=+70.5

Procedures to prepare the starting materialN-((1R,3S)-3-((4-iodo-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamideare described below:

Preparation ofN-((1R,3S)-3-((4-iodo-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide

HATU (219 mg, 0.58 mmol) was added to a solution of(1S,3R)-3-amino-N-(4-iodo-5-methylpyridin-2-yl)cyclohexanecarboxamidedihydrochloride (228 mg, 0.53 mmol; prepared according to Example 75),oxetane-3-carboxylic acid (59 mg, 0.58 mmol), TEA (0.24 mL, 1.7 mmol),DCM (2.8 mL) and DMF (2.8 mL) to give a colorless solution. The reactionturned yellow over time; after 4 h at r.t., the reaction wasconcentrated under reduced pressure and then diluted with DCM. Themixture was washed with water (3×50 mL), dried over sodium sulfate,filtered, concentrated under reduced pressure. The resulting residue wasadsorbed onto silica gel and purified by flash column chromatography,eluting with 0 to 10% MeOH and DCM to affordN-((1R,3S)-3-((4-iodo-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide(112 mg, 47%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)0.99-1.17 (1H, m), 1.20-1.37 (3H, m), 1.70-1.83 (3H, m), 1.84-1.94 (1H,m), 2.29 (3H, s), 2.54-2.64 (1H, m), 3.55-3.73 (2H, m), 4.54-4.64 (4H,m), 7.81 (1H, d), 8.16 (1H, s), 8.61 (1H, s), 10.45 (1H, s). m/z: ES+[M+H]+ 444.

Example 77:(1S,3R)-3-acetamido-N-(5-methyl-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

To a stirred solution of(1S,3R)-3-amino-N-(5-methyl-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(150 mg, 0.42 mmol), triethylamine (0.12 mL, 0.89 mmol) in DCM (10 mL)was added acetic anhydride (0.048 mL, 0.51 mmol). The reaction mixturewas stirred at r.t. for 4 h. Silica was added and the volatiles removedunder vacuum. The residue was purified by flash silica chromatography,eluting with 0.5% methanol in ethyl acetate to afford(1S,3R)-3-acetamido-N-(5-methyl-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(140 mg, 83%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆, 30° C.)1.04-1.11 (1H, m), 1.22-1.35 (3H, m), 1.7-1.94 (9H, m), 1.99-2.08 (2H,m), 2.23 (3H, s), 2.55-2.63 (1H, m), 2.75 (2H, t), 3.51-3.61 (1H, m),4.13 (2H, t), 7.62 (1H, s), 7.72 (1H, d), 7.96 (1H, s), 8.16 (1H, s),10.27 (1H, s). m/z: ES+ [M+H]+ 396.

Procedures used to prepare the starting material(1S,3R)-3-amino-N-(5-methyl-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of tert-butyl((1R,3S)-3-((5-methyl-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate

2nd Generation XPhos Precatalyst (86 mg, 0.11 mmol) was added to adegassed mixture of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine(324 mg, 1.31 mmol), tert-butyl((1R,3S)-3-((4-iodo-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)carbamate(500 mg, 1.09 mmol, prepared according to Example 47, Intermediate) andpotassium phosphate, tribasic, (569 mg, 3.27 mmol) in 1,4-dioxane (10mL) and water (1 mL). The mixture was degassed and was stirred at 85° C.for 24 h under nitrogen. The reaction mixture was cooled and silica wasadded. The mixture was concentrated under reduced pressure, and theresulting residue was purified by flash silica chromatography, elutingwith isocratic 60% ethyl acetate in heptane, to afford tert-butyl((1R,3S)-3-((5-methyl-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(220 mg, 45%) as a solid. ¹H NMR (400 MHz, DMSO, 30° C.) 1.05-1.14 (1H,m), 1.21-1.31 (3H, m), 1.38 (9H, s), 1.69-1.94 (7H, m), 1.96-2.08 (2H,m), 2.23 (3H, s), 2.54-2.61 (1H, m), 2.75 (2H, t), 4.13 (2H, t), 6.75(1H, br d), 7.62 (1H, s), 7.96 (1H, s), 8.16 (1H, s), 10.25 (1H, s).m/z: ES+ [M+H]+ 454.

Preparation of(1S,3R)-3-amino-N-(5-methyl-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

TFA (1 mL) was added to tert-butyl((1R,3S)-3-((5-methyl-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate(200 mg, 0.44 mmol) in DCM (10 mL). The mixture was stirred at r.t. for24 h, and the volatiles were removed under reduced pressure. Theresulting residue was purified by ion-exchange chromatography using anSCX column, eluting with 7N ammonia in methanol. Product fractions wereconcentrated under reduced pressure to afford(1S,3R)-3-amino-N-(5-methyl-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(150 mg, 96%) as a white solid. This material was used directly in thenext step without further purification. m/z: ES+ [M+H]+ 354.

Example 78:(1S,3R)-3-acetamido-N-(5-chloro-4-(7-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Unkown Mixture of Diastereomers as the Hydroxy Configuration is Unkown

Pyridine sulfur trioxide (40 mg, 0.25 mmol) was added to a solution of(1S,3R)-3-acetamido-N-(5-chloro-4-(5-(4-hydroxybutyl)-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexanecarboxamide(100 mg, 0.23 mmol, prepared in Example 78a) in 2:1 DCM:DMSO (4 mL) at0° C. After 2 h at 0° C. the reaction mixture was diluted with water andextracted with ethyl acetate (3×). The combined organic layers weredried over sodium sulfate, filtered, concentrated under reducedpressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 15% MeOH in DCM containing 0.2%triethylamine, to afford a white solid. This solid was triturated with10% DCM in hexanes to afford(1S,3R)-3-acetamido-N-(5-chloro-4-(7-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide(74 mg, 74%) as white foam solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)0.98-1.11 (1H, m), 1.18-1.41 (3H, m), 1.70-1.81 (6H, m), 1.85-2.18 (4H,m), 2.56-2.66 (1H, m), 2.67-2.91 (2H, m), 3.49-3.67 (1H, m), 4.23-4.40(1H, m), 5.54-5.73 (1H, m), 6.87 (1H, d), 7.75 (1H, d), 7.81 (1H, s),8.15 (1H, s), 8.39 (1H, s), 10.59 (1H, s). m/z: ES+ [M+H]+ 432.

Example 78a: Preparation of(1S,3R)-3-acetamido-N-(5-chloro-4-(5-(4-hydroxybutyl)-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexanecarboxamide

Hydrochloric acid in dioxane (4 M; 2.2 mL, 8.8 mmol) was added to asolution of(1S,3R)-3-acetamido-N-(4-(5-(4-((tert-butyldimethylsilyl)oxy)butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-5-chloropyridin-2-yl)cyclohexanecarboxamide(300 mg, 0.44 mmol) in methanol (3 mL). The reaction was stirred for 2 hat r.t. and then concentrated under reduced pressure. The resultingresidue was diluted with water (40 mL) and basified with sodiumbicarbonate. The mixture was then, saturated with sodium chloride andextracted with ethyl acetate (5×). The combined organic layers weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 30% methanol in DCM, to affordcrude(1S,3R)-3-acetamido-N-(5-chloro-4-(5-(4-hydroxybutyl)-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexanecarboxamide(163 mg, 83%) as a gum. ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 1.02-1.23 (1H,m), 1.24-1.47 (5H, m), 1.52-1.66 (2H, m), 1.75-1.88 (6H, m), 1.88-1.97(1H, m), 2.59-2.76 (3H, m), 3.35-3.43 (2H, m), 3.54-3.68 (1H, m),4.25-4.39 (1H, m), 7.66 (0.6H, s), 7.79 (1H, d), 7.92-8.02 (0.4H, m),8.12-8.21 (1H, m), 8.43 (1H, s), 10.62 (1H, s), 12.91 (0.4H, br s),12.98 (0.6H, br s)—2:3 ratio of pyrazole tautomers. m/z: ES+ [M+H]+ 434.

(1S,3R)-3-acetamido-N-(4-(5-(4-((tert-butyldimethylsilyl)oxy)butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-5-chloropyridin-2-yl)cyclohexanecarboxamideused as starting material was prepared as follows:

Preparation of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

NaH (60% wt in mineral oil; 1.85 g, 46.3 mmol) was added portionwise to1H-pyrazole (3.0 g, 44.1 mmol) in THF (30 mL) at 5° C. over a period of10 minutes under nitrogen. The resulting mixture was stirred at 5° C.for 30 minutes. SEM-Cl (8.2 mL, 46 mmol) was then added dropwise to thereaction. The resulting mixture was stirred at 5° C. for 1 hour. Thereaction mixture was then diluted with water (50 mL) and washedsequentially with Et₂O (3×50 mL). The combined organic layers were driedover magnesium sulfate, filtered and concentrated under reduced pressureto afford 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (6.5 g, 78%)as a faint yellow oil. ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 0.00 (s, 9H),0.79-0.95 (2H, m), 3.48-3.62 (2H, m), 5.45 (2H, s), 6.36 (1H, t), 7.56(1H, d), 7.91 (1H, d).

Preparation of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

Lithium magnesium 2,2,6,6-tetramethylpiperidin-1-ide dichloride (25.2mL, 27.7 mmol) was added dropwise to1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (5 g, 25 mmol) in THF(30 mL) at 21° C. under nitrogen. The resulting suspension was stirredat 21° C. for 1 hour. After 1.5 h the reaction was cooled to 0° C., andthen 1,2-dibromo-1,1,2,2-tetrachloroethane (8.21 g, 25.2 mmol) wasadded. The ice bath was removed, and the mixture was allowed to warm tor.t.; after 18 h, the reaction mixture was quenched with saturatedaqueous sodium chloride and extracted with ethyl acetate (2×). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby flash silica chromatography, elution gradient 0 to 40% ethyl acetatein hexanes, to afford5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (4.2 g, 60%) asa brown oil. ¹H NMR (DMSO-d₆, 27° C.) 0.00 (9H, s), 0.88-0.96 (2H, m),3.61 (2H, t), 5.49 (2H, s), 6.58 (1H, d), 7.67 (1H, d).

Preparation of5-(pent-4-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

3^(rd) Generation RuPhos Precatalyst (0.247 g, 0.30 mmol) was added to adegassed mixture of5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (4.1 g, 15mmol), pent-4-en-1-ylboronic acid (2.19 g, 19.2 mmol) and cesiumcarbonate (9.64 g, 29.6 mmol) in 1,4-dioxane (120 mL), and the reactionwas stirred at 90° C. for 18 h. The reaction mixture was cooled to r.t.and then diluted with water. Aqueous sodium bicarbonate was added, andthe resulting mixture was extracted with ethyl acetate (3×). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby flash silica chromatography, elution gradient 0 to 50% ethyl acetatein hexanes, to afford5-(pent-4-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.2g, 55%) as light yellow oil. ¹H NMR (DMSO-d₆, 27° C.) 0.00 (9H, s),0.75-0.93 (2H, m), 1.66-1.88 (2H, m), 2.15 (2H, q), 2.61-2.85 (2H, m),3.44-3.61 (2H, m), 4.92-5.22 (2H, m), 5.43 (2H, s), 5.89 (1H, ddt), 6.18(1H, d), 7.42 (1H, d).

Preparation of4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)butanal

5-(Pent-4-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(2.14 g, 8.03 mmol) was dissolved in DCM (40 mL) and cooled to −78° C.Ozone was bubbled through the solution for 12 minutes. The reaction wasthen purged of ozone using a stream of nitrogen, and triphenylphosphine(2.11 g, 8.03 mmol) was added. The reaction was allowed to warm to r.t.and was maintained under these conditions for 18 h before beingconcentrated under reduced pressure. The resulting residue was purifiedby flash silica chromatography, elution gradient 0 to 50% ethyl acetatein hexane, to afford4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)butanal (1.34 g,62%) as an oil. ¹H NMR (DMSO-d₆, 27° C.) 0.00 (9H, s), 0.76-0.94 (2H,m), 1.81-2.01 (2H, m), 2.57-2.60 (2H, m), 2.73 (2H, t), 3.42-3.64 (2H,m), 5.43 (2H, s), 6.20 (1H, d), 7.43 (1H, d), 9.74 (1H, t).

Preparation of4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)butan-1-ol

Sodium borohydride (0.372 g, 9.84 mmol) was added to a stirred solutionof 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)butanal (1.32g, 4.92 mmol) in methanol (20 mL) at 0° C. The resulting mixture wasstirred for 1 h under these conditions. The reaction was then dilutedwith water and extracted with ethyl acetate (2×). The combined organiclayers were dried over sodium sulfate, filtered, and concentrated underreduced pressure. The resulting crude residue was filtered through aplug of silica eluting with ethyl acetate. The filtrate was concentratedunder reduced pressure to afford4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)butan-1-ol (1.1g, 85%) as a light brown oil. ¹H NMR (DMSO-d₆, 27° C.) 0.00 (9H, s),0.86 (2H, t), 1.43-1.59 (2H, m), 1.61-1.79 (2H, m), 2.72 (2H, t),3.39-3.64 (4H, m), 4.43 (1H, t), 5.42 (2H, s), 6.16 (1H, d), 7.42 (1H,d). m/z: ES+ [M+H]+ 271.

Preparation of5-(4-((tert-butyldimethylsilyl)oxy)butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

TBS-Cl (0.94 g, 6.2 mmol) was added to a stirred solution of4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)butan-1-ol (1.1g, 4.1 mmol) and imidazole (0.85 g, 12 mmol) in DCM (20 mL) at 0° C.,and the reaction was stirred at r.t. for 18 h. The reaction mixture wasdiluted with water and extracted with EtOAc. The organic layer as driedover sodium sulfate, filtered, and concentrated under reduced pressure.The resulting residue was purified by flash silica chromatography,elution gradient 0 to 40% ethyl acetate in hexane, to give5-(4-((tert-butyldimethylsilyl)oxy)butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(1.5 g, 96%) as an oil. ¹H NMR (DMSO-d₆, 27° C.) 0.00 (9H, s), 0.09 (6H,s), 0.81-0.89 (2H, m), 0.92 (9H, s), 1.49-1.62 (2H, m), 1.65-1.80 (2H,m), 2.73 (2H, t), 3.47-3.61 (2H, m), 3.67 (2H, t), 5.43 (2H, s), 6.15(1H, d), 7.42 (1H, d). m/z: ES+ [M+H]+ 385.

Preparation of5-(4-((tert-butyldimethylsilyl)oxy)butyl)-4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

NIS (0.89 g, 4.0 mmol) was added to a stirred solution of5-(4-((tert-butyldimethylsilyl)oxy)butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(1.5 g, 4.0 mmol) in DCM (25 mL) at 0° C. The ice bath was removed, andthe reaction was stirred for 18 h under these conditions. The reactionmixture was diluted with water and extracted with EtOAc. The organiclayer was dried over sodium sulfate, filtered, and concentrated underreduced pressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 50% ethyl acetate in hexane, togive5-(4-((tert-butyldimethylsilyl)oxy)butyl)-4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(1.7 g, 85%) as a gum. 1H NMR (DMSO-d₆, 27° C.) 0.00 (9H, s), 0.07 (6H,s), 0.82-0.88 (2H, m), 0.91 (9H, s), 1.45-1.74 (4H, m), 2.75 (2H, t),3.48-3.60 (2H, m), 3.64 (2H, t), 5.48 (2H, s), 7.55 (1H, s).

Preparation of5-(4-((tert-butyldimethylsilyl)oxy)butyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

THF (16 mL) was added to5-(4-((tert-butyldimethylsilyl)oxy)butyl)-4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(800 mg, 1.57 mmol). The reaction was cooled to 0° C., andisopropylmagnesium chloride lithium chloride complex in THF (1.3 M; 1.57mL, 2.04 mmol) was added dropwise. The reaction was maintained underthese conditions for 30 minutes. Then2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.48 mL, 2.3 mmol)was added dropwise. The reaction was allowed to warm to r.t. and wasthen stirred under these conditions for 18 h. The reaction was dilutedwith water and extracted with ethyl acetate (2×). The combined organiclayers were dried over sodium sulphate, filtered, and concentrated underreduced pressure. The resulting residue was carried on to the next stepwithout purification. ¹H NMR (300 MHz, DMSO-d₆) 0.00 (9H, s), 0.05 (6H,s), 0.83-0.91 (11H, m), 1.30 (12H, s), 1.45-1.55 (2H, m), 1.55-1.69 (2H,m), 2.89 (2H, t), 3.48-3.69 (4H, m), 5.44 (2H, s), 7.54 (1H, s).

Preparation of(1S,3R)-3-acetamido-N-(4-(5-(4-((tert-butyldimethylsilyl)oxy)butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-5-chloropyridin-2-yl)cyclohexanecarboxamide

2nd Generation XPhos Precatalyst (28 mg, 0.04 mmol) was added to adegassed mixture of(1S,3R)-3-acetamido-N-(5-chloro-4-iodopyridin-2-yl)cyclohexanecarboxamide(300 mg, 0.71 mmol; prepared according to Example 12),5-(4-((tert-butyldimethylsilyl)oxy)butyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(472 mg, 0.92 mmol) and Cs₂CO₃ (695 mg, 2.13 mmol) in 1,4-dioxane (4 mL)and water (1 mL). The reaction mixture was stirred at 90° C. for 3 h andthen cooled and diluted with saturated aqueous sodium chloride. Themixture was extracted with ethyl acetate (2×) and the combined organiclayers were dried over sodium sulfate, filtered, and concentrated underreduced pressure. The resulting residue was, purified by flash silicachromatography, elution gradient 0 to 10% methanol in DCM, to afford(1S,3R)-3-acetamido-N-(4-(5-(4-((tert-butyldimethylsilyl)oxy)butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-5-chloropyridin-2-yl)cyclohexanecarboxamide(423 mg, 88%) as a light yellow gum (HPLC purity: 91%). ¹H NMR (DMSO-d₆,27° C.) −0.08 (6H, s), −0.05-−0.02 (9H, m), 0.75-0.79 (9H, m), 0.80-0.88(2H, m), 1.04-1.16 (1H, m), 1.20-1.40 (5H, m), 1.42-1.62 (2H, m), 1.76(6H, s), 1.90 (1H, d), 2.54-2.67 (1H, m), 2.76 (2H, t), 3.40-3.48 (2H,m), 3.51-3.62 (3H, m), 5.48 (2H, s), 7.62 (1H, s), 7.74 (1H, d), 8.12(1H, s), 8.40 (1H, s), 10.62 (1H, s). The multiplet at 1.04-1.16 ppm ispartially obscured by pinacol impurities. m/z: ES+ [M+H]+ 678.

Examples 79 and 80: Isomer 1 and Isomer 2 of(1S,3R)-3-acetamido-N-(5-chloro-4-(4-hydroxy-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide

Pure Enantiomers

The configuration of the hydroxy is unknown for Example 79 and 80 but isopposite in Example 79 vs Example 80

(1S,3R)-3-Acetamido-N-(4-(4-((tert-butyldimethylsilyl)oxy)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-chloropyridin-2-yl)cyclohexanecarboxamide(180 mg, 0.32 mmol) was resolved into diastereomeric components usingSFC conditions (Column: Chiralpak AS, 5 μm, 21.2 mm diameter, 250 mmlength, 75 mL/min flow rate over 8 min), eluting with 20% isopropanol inCO₂, to afford faster eluting isomer 1 of(1S,3R)-3-acetamido-N-(4-(4-((tert-butyldimethylsilyl)oxy)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-chloropyridin-2-yl)cyclohexanecarboxamide(49 mg, 27%) as a clear film and slower eluting isomer 2 of afford(1S,3R)-3-acetamido-N-(4-(4-((tert-butyldimethylsilyl)oxy)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-chloropyridin-2-yl)cyclohexanecarboxamide(42 mg, 22%) as a clear film.

Each isomer was then deprotected as follows: Hydrochloric acid indioxane (4 M; 0.500 mL, 14.40 mmol) was added dropwise to a solution ofeither isomer 1 (49 mg) or isomer 2 (42 mg) of(1S,3R)-3-acetamido-N-(4-(4-((tert-butyldimethylsilyl)oxy)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-chloropyridin-2-yl)cyclohexanecarboxamidein THF (2 mL). The resulting colorless solution was stirred at r.t. for18 h and then diluted with EtOAc (10 mL). The resulting mixture waswashed with saturated aqueous sodium bicarbonate and extracted withEtOAc (3×). The combined organic layers were concentrated under reducedpressure, and the resulting residue was adsorbed onto silica gel beforebeing purified by flash silica chromatography, elution gradient 0 to 10%methanol in DCM, to afford either isomer 1 (26 mg, 67%) or isomer 2 (16mg, 48%) of(1S,3R)-3-acetamido-N-(5-chloro-4-(4-hydroxy-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamideas a white solid.

Example 79, Isomer 1

¹H NMR (300 MHz, DMSO-d₆, 27° C.) 1.01-1.20 (7H, m), 1.20-1.34 (3H, m),1.67-1.85 (6H, m), 1.90 (1H, d), 2.58-2.66 (1H, m), 3.51-3.63 (1H, m),3.88 (1H, d), 4.00 (1H, d), 4.68 (1H, d), 5.53 (1H, d) 7.75 (1H, d),7.93 (1H, s), 8.37 (2H, d), 10.52 (1H, s). m/z: ES+ [M+H]+ 446.

Example 80, Isomer 2

¹H NMR (300 MHz, DMSO-d₆) 1.16 (7H, m), 1.22-1.38 (3H, m), 1.72-1.83(6H, m), 1.89 (1H, br d), 2.56-2.68 (1H, m), 3.47-3.66 (1H, m), 3.88(1H, d), 4.00 (1H, d), 4.68 (1H, d) 5.53 (1H, d) 7.75 (1H, br d), 7.93(1H, s), 8.37 (2H, s), 10.52 (1H, s). m/z: ES+ [M+H]+ 446.

Analytical SFC Conditions:

Column: Chiralpak AS

Column Dimensions: 5 m, 4.6 mm diameter, 50 mm length,

Mobile Phase A: CO₂ (100%)

Mobile Phase B: Isopropanol

Gradient: 10 to 60% Mobile Phase B

Flow Rate: 2.8 mL/min over 5 min

Column Temperature: 40° C. (100 bar)

Retention Time: 1.66 min, Example 79, Isomer 1

-   -   1.90 min, Example 80, Isomer 2        e.e. >96.4%, Example 79, Isomer 1    -   >98%, Example 80, Isomer 2

Procedures used to prepare the starting material(1S,3R)-3-acetamido-N-(4-(4-((tert-butyldimethylsilyl)oxy)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-chloropyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-ol

NaBH₄ (202 mg, 5.33 mmol) was added to a solution of5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-one (400 mg, 2.66mmol; prepared according to Example 14) in MeOH (12 mL) to give a whitemixture. The reaction was stirred under these conditions for 1 hour andthen quenched with water. The resulting mixture was extracted with DCM(25 mL) and then further extracted with 25% IPA in chloroform (50 mL).The combined organic layers were dried over sodium sulfate, filtered,concentrated under reduced pressure (405 mg, quantitative) to afford aclear oil. ¹H NMR (500 MHz, DMSO-d₆, 27° C.) 1.11 (6H, s), 3.75 (1H, d),3.91 (1H, d), 4.48 (1H, d), 5.49 (1H, d), 6.11 (1H, d), 7.42 (1H, s).m/z: ES+ [M+H]+ 153.

Preparation of4-((tert-butyldimethylsilyl)oxy)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

TBS-Cl (501 mg, 3.33 mmol) was added to a solution of5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-4-ol (405 mg, 2.66mmol), imidazole (362 mg, 5.32 mmol), and DCM (12 mL) to give a whitesuspension. The reaction was stirred at r.t. for 18 h and then dilutedwith DCM (100 mL) and washed with water and saturated aqueous sodiumchloride. The organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure before being adsorbed onto silicagel and purified by flash silica chromatography, elution gradient 0 to10% MeOH in DCM to afford4-((tert-butyldimethylsilyl)oxy)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(391 mg, 55%) as a clear oil. m/z: ES+ [M+H]+ 267.

Preparation of4-((tert-butyldimethylsilyl)oxy)-3-iodo-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

NIS (330 mg, 1.47 mmol) was added to a solution of4-((tert-butyldimethylsilyl)oxy)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(391 mg, 1.47 mmol) in DCM (3 mL) to give a red solution. The reactionwas stirred at r.t. under nitrogen for 18 h. The reaction was thendiluted with DCM (50 mL) and washed with water and saturated aqueoussodium chloride. The organic layer was dried over sodium sulfate,filtered, and concentrated under reduced pressure. The resulting residuewas purified by flash silica chromatography, elution gradient 0 to 10%methanol in DCM, to afford4-((tert-butyldimethylsilyl)oxy)-3-iodo-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(350 mg, 61%) as a red foam ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 0.19 (3H,s), 0.23 (3H, s) 0.87 (9H, s) 1.03 (3H, s) 1.12 (3H, s) 3.81 (1H, d)3.96 (1H, d) 4.52-4.63 (1H, s) 7.47 (1H, s). m/z: ES+ [M+H]+ 393.

Preparation of4-((tert-butyldimethylsilyl)oxy)-5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

Isopropylmagnesium chloride lithium chloride complex in THF (1.3 M; 0.89mL, 1.2 mmol) was added dropwise to a solution of4-((tert-butyldimethylsilyl)oxy)-3-iodo-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(350 mg, 0.89 mmol) in THF (2.2 mL) at 0° C. Then2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.273 mL, 1.34mmol) was added dropwise. The reaction was allowed to warm to r.t. andmaintained under these conditions for 18 h. The reaction was thendiluted with EtOAc (25 mL) and washed with saturated aqueous ammoniumchloride and saturated aqueous sodium chloride. The organic layer wasdried over sodium sulfate, filtered, and concentrated under reducedpressure to afford crude4-((tert-butyldimethylsilyl)oxy)-5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(290 mg, 83%) as a yellow foam solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)0.00 (3H, s), 0.19 (3H, s), 0.81 (9H, s), 0.92 (3H, s), 1.17 (3H, s),1.22 (6H, s), 1.24 (6H, s), 3.70 (1H, d), 3.91 (1H, d), 4.47 (1H, s),7.55 (1H, s). m/z: ES+ [M+H]+ 393.

Preparation of(1S,3R)-3-acetamido-N-(4-(4-((tert-butyldimethylsilyl)oxy)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-chloropyridin-2-yl)cyclohexanecarboxamide

Cesium carbonate (641 mg, 1.97 mmol) and 2nd Generation XPhosPrecatalyst (52 mg, 0.07 mmol) were added to a degassed mixture of4-((tert-butyldimethylsilyl)oxy)-5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(270 mg, 0.69 mmol) and(1S,3R)-3-acetamido-N-(5-chloro-4-iodopyridin-2-yl)cyclohexanecarboxamide(276 mg, 0.66 mmol; prepared according to Example 12) in 1,4-dioxane(5.4 mL) and water (1.1 mL). The reaction was then warmed to 85° C. andmaintained under these conditions for 18 h before being diluted withEtOAc, washed with water, brine, concentrated under reduced pressure.The resulting residue was adsorbed onto silica gel and purified by flashsilica chromatography, elution gradient 0 to 10% MeOH in DCM to afford(1S,3R)-3-acetamido-N-(4-(4-((tert-butyldimethylsilyl)oxy)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-chloropyridin-2-yl)cyclohexanecarboxamide(180 mg, 49%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.) −0.38(3H, d), 0.00 (3H, s), 0.71 (9H, s), 1.03-1.47 (10H, m), 1.76-2.01 (7H,m), 2.61-2.75 (1H, m), 3.51-3.72 (1H, m), 3.96 (1H, d), 4.06 (1H, d),4.87 (1H, s), 7.79-7.87 (2H, m), 8.32 (1H, s), 8.46 (1H, s), 10.67 (1H,br s). m/z: ES+ [M+H]+ 560.

Example 81:(1R,3S)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide

Cesium carbonate (482 mg, 1.48 mmol) and 2nd Generation XPhosPrecatalyst (15 mg, 0.02 mmol) were added to a degassed mixture of5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(142 mg, 0.54 mmol; prepared according to Example 23),(1R,3S)-3-acetamido-N-(5-fluoro-4-iodopyridin-2-yl)cyclohexanecarboxamide(200 mg, 0.49 mmol), dioxane (4.1 mL), and water (0.8 mL). The reactionwas maintained at 95° C.; after 4 h, additional5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(100 mg) was added. The reaction was maintained under these conditionsfor another 18 h, cooled, and then diluted with EtOAc (150 mL) andwashed with water and saturated aqueous sodium chloride. The organiclayer was then dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The resulting residue was adsorbed onto silicagel and purified by flash silica chromatography, elution gradient 0 to100% ethyl acetate in hexanes followed by 0 to 10% MeOH in EtOAc, toafford a beige solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.) 0.98-1.19 (1H,t), 1.19-1.41 (9H, m), 1.73-1.83 (6H, m), 1.90 (1H, br d), 2.56-2.69(1H, m), 2.93 (3H, s), 3.50-3.64 (1H, m), 3.94 (2H, s), 7.75 (1H, d),7.88 (1H, d), 8.28 (1H, d)), 8.30 (1H, d), 10.46 (1H, s). m/z: ES+[M+H]+ 414.

Optical Rotation:

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 25° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: MeOH

[α]=−101

Procedures used to prepare the starting material(1R,3S)-3-acetamido-N-(5-fluoro-4-iodopyridin-2-yl)cyclohexanecarboxamideare described below:

Preparation of tert-butyl((1S,3R)-3-((5-fluoro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate

1-Chloro-N,N,2-trimethylprop-1-en-1-amine (489 μL, 3.70 mmol) was addeddropwise to a solution of(1R,3S)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (660mg, 2.7 mmol; prepared according to Example 25 substituting(1R,3S)-benzyl 3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate for(1S,3R)-benzyl 3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate) inDCM (6.3 mL). After 1 hour, a solution of 5-fluoro-4-iodopyridin-2-amine(587 mg, 2.47 mmol; prepared according to Example 54) and pyridine (400μL, 4.9 mmol) in DCM (6 mL) was added. After 18 h, the reaction wasdiluted with DCM (200 mL) and washed with water and saturated aqueoussodium chloride. The organic layer was dried over sodium sulfate,filtered, and concentrated under reduced pressure. The resulting residuewas adsorbed onto silica and purified by flash silica chromatography,elution gradient 0 to 10% methanol in DCM, to afford tert-butyl((1S,3R)-3-((5-fluoro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate(1.10 g, 96%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.02-1.18 (1H, m), 1.19-1.35 (3H, m), 1.38 (10H, s), 1.62-1.81 (3H, m),1.82-1.94 (1H, m), 2.56-2.71 (1H, m), 3.48-3.59 (1H, m), 6.78 (1H, d),8.25 (1H, s), 8.60 (1H, d), 10.59 (1H, s). m/z: ES+ [M+Na]+ 486.

Preparation of(1R,3S)-3-acetamido-N-(5-fluoro-4-iodopyridin-2-yl)cyclohexanecarboxamide

Hydrochloric acid in dioxane (4 M; 2.7 mL, 11 mmol) was added to asolution of tert-butyl((1S,3R)-3-((5-fluoro-4-iodopyridin-2-yl)carbamoyl)cyclohexyl)carbamate(500 mg, 1.08 mmol) in methanol (8.97 mL) at r.t. After stirring underthese conditions for 19 h, the reaction was concentrated under reducedpressure. Triethylamine (750 μL, 5.4 mmol) and acetic anhydride (200 μL,2.2 mmol) were added to the resulting residue. The reaction was stirredunder these conditions for 1 hour and then diluted with DCM (100 mL).The resulting mixture was washed with 1N aqueous HCl, water, andsaturated aqueous sodium chloride. The organic layer was then dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresulting residue was adsorbed onto silica gel and purified by flashsilica chromatography, elution gradient 0 to 100% ethyl acetate inhexane followed by 0 to 10% methanol in ethyl acetate, to afford(1R,3S)-3-acetamido-N-(5-fluoro-4-iodopyridin-2-yl)cyclohexanecarboxamide(200 mg, 46%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆, 27° C.)1.00-1.17 (1H, m), 1.20-1.40 (3H, m), 1.71-1.82 (6H, m), 1.83-1.92 (1H,m) 2.54-2.64 (1H, m) 3.48-3.58 (1H, m) 7.76 (1H, d) 8.25 (1H, s) 8.61(1H, d) 10.61 (1H, s). m/z: ES+ [M+H]+ 406.

Example 82a: Preparation of(1S,3R)-3-acetamido-N-(5-chloro-4-(5-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1-carboxamide

Hydrochloric acid in dioxane (4 M, 0.27 mL, 1.09 mmol) was added to asolution containing a 7:3 ratio of unidentified pyrazole isomers of(1S,3R)-3-acetamido-N-(4-(3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-5-chloropyridin-2-yl)cyclohexane-1-carboxamideand(1S,3R)-3-acetamido-N-(4-(5-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-5-chloropyridin-2-yl)cyclohexane-1-carboxamide(0.75 g, 1.1 mmol) in methanol (2 mL). After 4 h the reaction was storedin the freezer for 6 days, and then concentrated under reduced pressure.The resulting residue was basified with saturated aqueous sodiumbicarbonate and the resulting mixture was extracted with ethyl acetate(×2). The combined organic layers were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The resulting residuewas purified by flash silica chromatography, elution gradient 0 to 40%methanol in ethyl acetate, to afford(1S,3R)-3-acetamido-N-(5-chloro-4-(5-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1-carboxamide(0.48 g, 98%) as a white solid. ¹H NMR (DMSO-d₆ 27° C.) 0.49-0.66 (m,6H), 0.97-1.13 (1H, m), 1.27 (3H, d), 1.71-1.83 (6H, m), 1.89 (1H, d),2.54-2.70 (3H, m), 2.93-3.06 (2H, m), 3.45-3.66 (1H, m), 4.34 (0.3H, brs), 4.45-4.64 (0.7H, m), 7.54 (0.7H, br s), 7.74 (1H, d), 7.87 (0.3H, brs), 8.08 (1H, s), 8.39 (1H, s), 10.55 (1H, s), 12.77 (0.7H, br s), 12.89(0.3H, br s). m/z: ES+ [M+H]+ 448.

Optical Rotation:

Concentration: 0.1 g/dL

Lamp: Sodium

Wavelength: 589 nm

Temperature: 25° C.

Path length: 10 cm

Cell volume: 1 mL

Solvent: DMSO

[α]=+72

Procedures to prepare the starting material mixture of(1S,3R)-3-acetamido-N-(4-(3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-5-chloropyridin-2-yl)cyclohexane-1-carboxamideand(1S,3R)-3-acetamido-N-(4-(5-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-5-chloropyridin-2-yl)cyclohexane-1-carboxamideare described below:

Preparation of ethyl 1-benzyl-1H-pyrazole-3-carboxylate

Sodium hydride (60 wt % in mineral oil; 3.14 g, 78.5 mmol) was added toa solution of ethyl 1H-pyrazole-3-carboxylate (10 g, 71.4 mmol), benzylbromide (12.7 mL, 107 mmol), and DMF (100 mL) at 0° C. portionwise over3 min with vigorous stirring. The mixture was allowed to warm to r.t.over 18 h and then diluted with ethyl acetate. The resulting mixture waswashed with water (×3) and saturated aqueous sodium chloride. Theorganic layer was then dried over sodium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography, elution gradient 0 to 50% ethyl acetatein hexanes, to afford ethyl 1-benzyl-1H-pyrazole-3-carboxylate (11.3 g,69%) as a slower eluting amber oil. Also isolated was ethyl1-benzyl-1H-pyrazole-5-carboxylate (2.69 g, 16.4%) as a light amber oil.

Ethyl 1-benzyl-1H-pyrazole-3-carboxylate

¹H NMR (DMSO-d₆27° C.) 1.28 (3H, t), 4.25 (2H, q), 5.43 (2H, s), 6.77(1H, d), 7.23-7.42 (5H, m), 7.97 (1H, d). m/z: ES+ [M+H]+ 231.

Preparation of 1-benzyl-1H-pyrazole-3-carboxylic acid

Lithium hydroxide (1.3 g, 56 mmol) was added to a solution of ethyl1-benzyl-1H-pyrazole-3-carboxylate (11.3 g, 49.1 mmol) intetrahydrofuran (55 mL), water (19 mL), and methanol (19 mL). Afterstirring under these conditions for 1.5 h, the reaction was poured intoethyl acetate and quenched with aqueous hydrochloric acid (1N; 57 mL, 57mmol). The mixture was washed with saturated aqueous sodium chloride,and the organic layer was dried over sodium sulfate, filtered, andconcentrated under reduced pressure to afford an oily white solid. Thissolid was taken up in minimal DCM and then diluted with 50% ether inhexanes. After stirring vigorously for 15 min the mixture was filteredto afford 1-benzyl-1H-pyrazole-3-carboxylic acid (3.78 g, 38%) as awhite crystalline solid.

Additional aqueous hydrochloric acid (1N) was added to the combinedaqueous layers until the mixture was at pH 5. Then the combined aqueouslayers were extracted with ethyl acetate (×3), and the combined organiclayers were dried over sodium sulfate, filtered, and concentrated underreduced pressure. The resulting solid was taken up in hexanes andstirred vigorously for 10 min. Upon filtration, the resultingcrystalline white solid was dried under vacuum to afford additional1-benzyl-1H-pyrazole-3-carboxylic acid (5.3 g, 53%) as a whitecrystalline solid. ¹H NMR (DMSO-d₆, 27° C.) 5.40 (2H, s), 6.69 (1H, d),7.22-7.41 (5H, m), 7.92 (1H, d), 12.07-13.22 (1H, br s). m/z: ES+ [M+H]+203.

Preparation of 1-bromo-3-methylbut-2-ene lithium chloride

Following the procedures of Samann & Knochel (Synthesis, 2013, 45,1870), lithium chloride (1.78 g, 42.0 mmol) in a flame dried flask wasdried under vacuum with a heat gun for 5 min. Upon cooling, zinc powder(5.0 g, 77 mmol) was added followed by THF (37 mL). After stirringvigorously for 5 min, 1,2-dibromoethane (0.19 mL, 2.2 mmol) and thenTMS-Cl (0.39 mL, 3.1 mmol) were added. The resulting mixture was allowedto stir at r.t. for 2 min and then immersed in a water bath. A lightbrown solution of 1-bromo-3-methylbut-2-ene (4 mL, 35 mmol) in THF (37mL) was added dropwise over 30 min, and the water bath was removed. Theblack mixture was maintained under these conditions for 1.5 h and thenstirring was stopped. The mixture was allowed to settle over 18 h andthen used directly without further purification.

Preparation 1-benzyl-1H-pyrazole-3-carbonyl chloride

Two drops of DMF were added to a mixture of1-benzyl-1H-pyrazole-3-carboxylic acid (5.26 g, 26.0 mmol) and oxalylchloride (3.4 mL, 39 mmol) in DCM (100 mL). After 4 h, the now clearlight yellow solution was concentrated under reduced pressure, and theresulting yellow-orange oil was dried under vacuum with heating (heatgun) to remove excess oxalyl chloride. The now dark orange/amber oil wasused directly without further purification.

Preparation of 1-(1-benzyl-1H-pyrazol-3-yl)-2,2-dimethylbut-3-en-1-one

(3-Methylbut-2-en-1-yl)zinc(II) bromide lithium chloride (77 mL, 32.5mmol) in THF (as described above) was added dropwise to a yellowsolution of 1-benzyl-1H-pyrazole-3-carbonyl chloride (5.74 g, 26.0 mmol)in tetrahydrofuran (53 mL) at −78° C. After 45 min the reaction wasquenched with 50% saturated aqueous sodium chloride, and the layers wereseparated. The aqueous layer was extracted with ethyl acetate, and thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography, elution gradient 0 to 50% ethyl acetatein hexanes, to afford1-(1-benzyl-1H-pyrazol-3-yl)-2,2-dimethylbut-3-en-1-one (5.2 g, 79%) asa clear faint amber oil. Impure product fractions were concentratedunder reduced pressure and repurified using the same conditions toafford additional 1-(1-benzyl-H-pyrazol-3-yl)-2,2-dimethylbut-3-en-1-one(0.81 g, 12%) as a faint amber oil. ¹H NMR (DMSO-d₆, 27° C.) 1.40 (6H,s), 5.02 (1H, dd), 5.07 (1H, dd), 5.43 (2H, s), 6.44 (1H, dd), 6.71 (1H,d), 7.25-7.40 (5H, m), 7.89 (1H, d). m/z: ES+ [M+H]+ 255.

Preparation of 1-benzyl-3-(2,2-dimethylbut-3-en-1-yl)-1H-pyrazole

Hydrazine monohydrate (5.1 mL, 67 mmol) was added to a solution of1-(1-benzyl-1H-pyrazol-3-yl)-2,2-dimethylbut-3-en-1-one (3.42 g, 13.45mmol) and 2,2′-oxybis(ethan-1-ol) (35 mL, 369 mmol) at 120° C. Thereaction was then warmed to 180° C. and aqueous potassium hydroxide (3.8ml, 67 mmol) was added cautiously and followed by 8 KOH chips. After 1hour, another 4 KOH chips were added. The reaction was maintained underthese conditions for another 2 h and then cooled to r.t. and dilutedwith water. The mixture was extracted with ether (×3). The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. There resulting residue waspurified by column chromatography, elution gradient 0 to 30% ethylacetate in hexanes, to afford1-benzyl-3-(2,2-dimethylbut-3-en-1-yl)-1H-pyrazole (2.72 g, 84%) as aclear colorless oil. ¹H NMR (DMSO-d₆, 27° C.) 0.96 (6H, s), 4.85 (1H,s), 4.88-4.93 (1H, m), 5.26 (2H, s), 5.83-5.94 (1H, m), 6.02 (1H, d),7.12-7.17 (2H, m), 7.22-7.35 (3H, m), 7.64 (1H, d). A 2H multiplet isburied under the DMSO signal. m/z: ES+ [M+H]+ 241.

Preparation of 3-(1-benzyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol

Ozone was bubbled through a solution of1-benzyl-3-(2,2-dimethylbut-3-en-1-yl)-1H-pyrazole (2.7 g, 11 mmol) inmethanol (45 mL) at −78° C. for 30 min, resulting in a lightyellow-green solution. Then sodium borohydride (1.1 g, 28 mmol) wasadded, and the reaction was allowed to warm to r.t. After 15 min,another 200 mg of sodium borohydride were added, and the reaction wasmaintained under these conditions for a further 20 min. Then thereaction was concentrated under reduced pressure and quenched withconcentrated aqueous HCl (4.5 mL). The resulting white mixture wasdiluted with water and ethyl acetate and basified with potassiumcarbonate until pH 8. The layers were separated, and the aqueous layerwas extracted with ethyl acetate (×3). The combined organic layers werewashed with saturated aqueous sodium chloride and dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Theresulting residue was taken up in DCM and purified by flash silicachromatography, elution gradient 0 to 100% ethyl acetate in hexanes) toafford 3-(1-benzyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (2.14 g,78%) as a clear colorless oil. ¹H NMR (DMSO-d₆, 27° C.) 0.78 (6H, s),2.42 (2H, s), 3.11 (2H, d), 4.44 (1H, t), 5.26 (2H, s), 6.04 (1H, d),7.12-7.19 (2H, m), 7.23-7.36 (3H, m), 7.65 (1H, d). m/z: ES+ [M+H]+ 245.

Preparation of 2,2-dimethyl-3-(1H-pyrazol-3-yl)propan-1-ol

A degassed mixture of3-(1-benzyl-1H-pyrazol-3-yl)-2,2-dimethylpropan-1-ol (2.10 g, 8.59mmol), aqueous hydrochloric acid (1N; 3.9 mL, 3.9 mmol), and 20 wt %Pd(OH)₂ on carbon (0.151 g, 0.21 mmol) was subjected to a hydrogenatmosphere and warmed to 50° C. After 2 h, the reaction was filteredwhile still warm with a methanol wash. The clear colorless filtrate wasconcentrated under reduced pressure to a light yellow oil, which wasthen reconcentrated from toluene (×3). This afforded a light yellow gum(0.45 equiv HCl salt) which was used in the next step without furtherpurification. ¹H NMR (DMSO-d₆, 27° C.) 0.79 (6H, s), 2.55 (2H, s), 3.11(2H, s), 6.18 (1H, d), 7.70 (1H, d), 9.63 (1H, br s). OH and HCl signalsnot observed. m/z: ES+ [M+H]+ 155.

Preparation of3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1H-pyrazole

TBS-Cl (50 wt % in toluene; 4.5 mL, 13 mmol) was added dropwise to asolution of crude 2,2-dimethyl-3-(1H-pyrazol-3-yl)propan-1-ol (0.45molar HCl salt; 1.47 g, 8.59 mmol) and imidazole (1.75 g, 25.8 mmol) inDCM (81 mL) at r.t. After 15 min, another 1 mL of TBS-Cl in toluene wasadded. The white mixture was maintained under these conditions for 1.5 hand then poured into saturated aqueous sodium bicarbonate. The layerswere separated, and the aqueous layer was extracted with DCM (2×). Thecombined organic layers were washed with saturated aqueous sodiumchloride, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The resulting clear colorless oil was purified byflash silica chromatography, elution gradient 0 to 60% ethyl acetate inhexane, to afford3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1H-pyrazole(2.13 g, 92%) as a clear faint yellow oil. ¹H NMR (DMSO-d₆, 27° C.) 0.00(s, 6H), 0.75 (6H, s), 0.86 (9H, s), 3.22 (2H, s), 5.92 (1H, br s),7.08-7.67 (1H, m), 12.35 (1H, br s). m/z: ES+ [M+H]+ 269.

Preparation of3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolecompound and5-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

Isolated as a 2:3 Ratio of Unidentified SEM-Protected Isomers

Sodium hydride (60 wt % in mineral oil; 0.381 g, 9.52 mmol) was added inone portion to a solution of3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1H-pyrazole(2.13 g, 7.93 mmol) in DMF (11 mL) at 0° C. After 5 min,(2-(chloromethoxy)ethyl)trimethylsilane (SEM-Cl; 1.8 mL, 9.5 mmol) wasadded dropwise. After 10 min, another 100 μL of SEM-Cl were added alongwith 20 mg of NaH (60 wt % suspension in mineral oil). After a final 15min, the reaction was quenched with saturated aqueous sodium bicarbonateand diluted with ethyl acetate. The layers were separated, and theorganic layer was washed with 50% saturated aqueous sodium chloride (×2)and then saturated aqueous sodium chloride. The organic layer was driedover sodium sulfate, filtered, and concentrated under reduced pressureto a clear colorless oil. This oil was purified by flash silicachromatography, elution gradient 0 to 20% ethyl acetate in hexanes, toafford an unseparated mixture of3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolecompound and5-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(2.58 g, 81.6%) as a 2:3 ratio of unidentified SEM-protected isomers anda clear colorless oil. ¹H NMR (DMSO-d₆, 27° C.) −0.09-(−0.05) (9H, m),0.02-0.07 (6H, m), 0.77-0.84 (8H, m), 0.89 (9H, s), 2.44 (1.2H, s), 2.65(0.8H, s), 3.23 (0.8H, m), 3.27 (1.2H, m), 3.48 (2H, t), 5.31 (1.2H, s),5.40 (0.8H, s), 6.05 (0.6H, d), 6.09 (0.4H, d), 7.40 (0.4H, d), 7.71(0.6H, d). m/z: ES+ [M+H]+ 399

Preparation of3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolecompound and5-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

Isolated as a 2:3 ratio of unidentified SEM-protected isomers NIS (1.78g, 7.91 mmol) was added to a solution of an unidentified 2:3 mixture of3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolecompound and5-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(2.58 g, 6.48 mmol) in acetonitrile (34 mL). After 18 h, another 1.8 gof NIS was added, and the reaction was warmed to 50° C. After 4 h,another 400 mg of NIS was added. After another 4 h, the reaction wasallowed to cool to r.t. and was maintained under these conditions for 18h. The reaction was then poured into 50% saturated aqueous sodiumchloride and titrated with sodium thiosulfate until all dark red-ambercolor disappeared. The layers were separated, and the organic layer waswashed with saturated aqueous sodium chloride. The organic layer wasthen dried over sodium sulfate, filtered, and concentrated under reducedpressure. The resulting residue was purified by flash columnchromatography, elution gradient 0 to 15% ethyl acetate in hexanes, toafford3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolecompound and5-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(2.93 g, 86%) as a 2:3 mixture of unidentified SEM-protected isomers anda light yellow oil. ¹H NMR (DMSO-d₆, 27° C.) −0.09-(−0.05) (9H, m),0.02-0.06 (6H, m), 0.76-0.92 (17H, m), 2.45 (1.2H, s), 2.71 (0.8H, s),3.29-3.32 (0.8H, m), 3.34-3.37 (1.2H, m), 3.50 (2H, td), 5.33 (1.2H, s),5.47 (0.8H, s), 7.56 (s, 0.4H), 7.96 (0.6H, s). m/z: ES+ [M+H]+ 525.

Preparation of3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-H-pyrazolecompound and5-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-H-pyrazole

Isolated as an 3:2 ratio of SEM-protected isomers as shownIsopropylmagnesium chloride lithium chloride complex in THF (1.3 M; 6.45mL, 8.39 mmol) was added dropwise to a solution of a 2:3 unidentifiedmixture of3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolecompound and5-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(2.93 g, 5.59 mmol) in THF (40 mL) at −78° C. After 1 hour,2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.8 mL, 8.9 mmol)was added dropwise, and the reaction was allowed to stir under theseconditions for 2 h. Then the reaction was immersed in an ice bath (0°C.). After another 2 h, the reaction was poured into saturated aqueousammonium chloride. The mixture was extracted with ethyl acetate (3×),and the combined organic layers were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The resulting residuewas purified by flash silica chromatography, elution gradient 0 to 10%ethyl acetate in hexanes over 20 min) to afford an identified 3:2mixture of3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazoleand5-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(2.37 g, 80%) as a clear colorless oil. ¹H NMR (DMSO-d₆, 27° C.)−0.09-(−0.05) (9H, m), 0.01-0.06 (6H, m), 0.73-0.84 (8H, m), 0.87-0.92(9H, m), 1.24 (12H, s), 2.63 (1.2H, s), 2.85 (0.6H, s), 3.26 (0.8H, s),3.33 (1.2H, s), 3.50 (2H, t), 5.33 (1.2H, s), 5.43 (8H, s), 7.54 (4H,s), 7.91 (0.6H, s). m/z: ES+ [M+H]+ 525.

Preparation of(1S,3R)-3-acetamido-N-(4-(3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-5-chloropyridin-2-yl)cyclohexane-1-carboxamideand(1S,3R)-3-acetamido-N-(4-(5-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-5-chloropyridin-2-yl)cyclohexane-1-carboxamide

Isolated as a 3:7 Ratio of SEM-Protected Isomers

PdCl₂(dppf) (DCM adduct; 0.061 g, 0.07 mmol) and cesium carbonate (1.45g, 4.46 mmol) were added to a degassed mixture of(1S,3R)-3-acetamido-N-(5-chloro-4-iodopyridin-2-yl)cyclohexane-1-carboxamide(0.74 g, 1.49 mmol; prepared according to Example 12), a 3:2 mixture of3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazoleand5-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(0.813 g, 1.55 mmol), 1,4-dioxane (12 mL), and water (2.5 mL). Themixture was warmed to 93° C. and maintained under these conditions for18 h. The reaction was then cooled, diluted with ethyl acetate, andwashed with saturated aqueous sodium chloride. The organic layer wasdried over sodium sulfate, filtered, and concentrated under reducedpressure. The resulting black-green residue was purified by flash silicachromatography, elution gradient 50 to 100% ethyl acetate in hexane then0 to 10% methanol in ethyl acetate, to afford(1S,3R)-3-acetamido-N-(4-(3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-5-chloropyridin-2-yl)cyclohexane-1-carboxamideand(1S,3R)-3-acetamido-N-(4-(5-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-5-chloropyridin-2-yl)cyclohexane-1-carboxamide(0.75 g, 73%) in a 3:7 ratio of unidentified SEM-protected isomers as alight amber glass. ¹H NMR (DMSO-d₆, 27° C.) −0.06-0.02 (15H, m), 0.61(1.7H, s), 0.72 (4.3H, s), 0.81 (6.3H, s), 0.84-0.93 (4.7H, m),1.04-1.22 (1H, m), 1.22-1.40 (3H, m), 1.71-1.87 (6H, m), 1.88-1.98 (1H,m), 2.58-2.73 (2.4H, m), 2.91 (0.6H, s), 3.12 (0.6H, s), 3.19 (1.4H, s),3.55-3.67 (3H, m), 5.46 (1.3H, s), 5.57 (0.7H, s), 7.66 (0.3H, s), 7.78(1H, d), 8.09 (0.7H, s), 8.12-8.15 (0.3H, s), 8.15-8.17 (0.7H, s),8.42-8.44 (0.7H, s), 8.46 (0.3H, s), 10.64 (1H, s). m/z: ES+ [M+H]+ 692.

Example 82: Preparation of(1S,3R)-3-acetamido-N-(5-chloro-4-(6-hydroxy-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexane-1-carboxamide

Unknown Mixture of Diastereomers as the Hydroxy Configuration is Unknown

Pyridine sulfur trioxide (0.30 g, 1.9 mmol) was added to a solution of(1S,3R)-3-acetamido-N-(5-chloro-4-(5-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1-carboxamide(0.48 g, 1.1 mmol, prepared in Example 82a) in DCM (6.8 mL) anddimethylsulfoxide (3.4 mL) at 0° C. The resulting solution wasmaintained under these conditions for 15 minutes and then poured intoethyl acetate and saturated aqueous ammonium chloride. The layers wereseparated and the organic layer was washed with 50% saturated aqueoussodium chloride and then 100% saturated aqueous sodium chloride. Theorganic layer was dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The resulting turbid residue was taken up in DCMand purified by flash silica chromatography, elution gradient 0 to 40%methanol in ethyl acetate, to afford a white foam solid (460 mg). Thissolid was further purified by preparative HPLC (Waters XBridge PhenylPrep column, 5μ silica, 19 mm diameter, 100 mm length), usingdecreasingly polar mixtures of water (containing 0.2% NH₄OH, pH 10) andmethanol as eluents. Fractions containing the desired compound wereconcentrated under reduced pressure to afford(1S,3R)-3-acetamido-N-(5-chloro-4-(6-hydroxy-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexane-1-carboxamide(255 mg, 53%) as a white foam solid. ¹H NMR (DMSO-d₆, 27° C.) 0.99-1.16(4H, m), 1.20 (3H, s), 1.23-1.40 (3H, m), 1.73-1.83 (6H, m), 1.89 (1H,d), 2.56-2.68 (1H, m), 2.75 (1H, d), 2.95 (1H, d), 3.50-3.63 (1H, m),5.25 (1H, s), 6.92 (1H, br s), 7.75 (1H, d), 8.04 (1H, s), 8.25 (1H, s),8.36 (1H, s), 10.56 (1H, s). m/z: ES+ [M+H]+ 446.

Examples 83 and 84: Preparation of(1R,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamideand(1S,3S)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide

Examples 83 and 84 are Pure Enantiomers

The absolute configuration for Examples 83 and 84 are unknown, but areopposite from one another. Relative configuration is trans for bothExamples 83 and 84.

Triethylamine (0.29 mL, 2.1 mmol) and acetic anhydride (0.066 mL, 0.70mmol) were added to racemictrans-3-amino-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide(0.24 g, 0.64 mmol) in DCM (4 mL). After stirring at r.t. for 1 hour,the mixture was washed with water and concentrated under reducedpressure. The resulting residue was purified by flash silicachromatography, elution gradient 0 to 10% MeOH in DCM, to afford racemictrans-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide(0.270 g) as a colourless oil. The racemic material was resolved bypreparative HPLC (Phenomonex Lux C4 column, 20 am silica, 50 mmdiameter, 250 mm length), using a 70/30 mixture of Heptane/IPA as eluentat 120 mL/min. Fractions containing isomer 1 (faster eluting) and isomer2 (slower eluting) were evaporated to dryness. Isomer 1 (114 mg) wasrepurified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μsilica, 30 mm diameter, 100 mm length), using decreasingly polarmixtures of water (containing 1% NH₃) and MeCN as eluents to affordisomer 1 oftrans-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide(0.081 g, 31%).

Isomer 2 oftrans-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide(0.090 g, 34%) was isolated from the first chiral preparativepurification.

Example 83, Isomer 1

¹H NMR (400 MHz, DMSO-d₆, 30° C.) 1.29 (6H, s), 1.45-1.83 (9H, m), 1.86(3H, s), 2.71-2.84 (1H, m), 2.94 (2H, s), 3.94 (2H, s), 7.54 (1H, d),7.89 (1H, d), 8.22-8.34 (2H, m), 10.30 (1H, s). m/z: ES+ [M+H]+ 414.

Example 84, Isomer 2

¹H NMR (400 MHz, CDCl₃, 30° C.) 1.35 (6H, s), 1.44-1.92 (7H, m),1.95-2.04 (4H, m), 2.54 (1H, s), 3.02 (2H, s), 3.94 (2H, s), 4.17-4.35(1H, m), 5.57 (1H, d), 8.01 (1H, d), 8.08 (2H, d), 8.34 (1H, d). m/z:ES+ [M+H]+ 414.

Analytical Chiral Conditions:

Column: Chiralpak IA column ID-2

Column Dimensions: 5 μm, 4.6 mm diameter, 250 mm length,

Mobile Phase A: Heptane

Mobile Phase B: Isopropanol

Gradient: Isocratic 30% Mobile Phase B

Flow Rate: 2 mL/min over 15 min

Retention Time: 6.34 min, Example 83, Isomer 1

-   -   8.93 min, Example 84, Isomer 2        e.e. >98% (both isomers)

Procedures used to prepare racemictrans-3-amino-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamideare described below:

Preparation of racemictrans-3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid

A solution of racemic trans-3-aminocyclohexanecarboxylic acidhydrochloride (2.00 g, 11.1 mmol) and N-ethyl-N-isopropylpropan-2-amine(7.9 mL, 44 mmol) in 1,4-dioxane (16 mL) and water (16 mL) was cooled to0° C. Di-tert-butyl dicarbonate (2.67 g, 12.25 mmol) was then addedportionwise to the reaction mixture, which was allowed to warm to r.t.after the final portion was added. The reaction mixture was then cooledto 0° C., and 2 M aqueous hydrochloric acid was added to adjust the pHto 2. The reaction mixture was extracted with EtOAc (2×200 mL), and thecombined organic layers were washed with water (100 mL) and dried overNa₂SO₄. The resulting mixture was filtered, and the filtrate wasconcentrated under reduced pressure. The resulting white solid was driedunder vacuum for 18 h to afford racemictrans-3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (2.73g, 101%). ¹H NMR (400 MHz, DMSO-d₆, 30° C.) 1.25-1.33 (1H, m), 1.39 (9H,s), 1.45-1.61 (6H, m), 1.71-1.81 (1H, m), 2.58-2.69 (1H, m), 3.55 (1H,br s), 6.71 (1H, br s), 12.03 (1H, br s).

Preparation of racemic tert-butyltrans-(-3-carbamoylcyclohexyl)carbamate

CDI (3.14 g, 19.39 mmol) was added to a solution of racemictrans-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (1.73 g,7.11 mmol) in DMF (15 mL) at 40° C. The resulting mixture was maintainedunder these conditions for 4 h. The reaction mixture was then cooled to0° C. and acetic acid ammonia salt (3.49 g, 45.3 mmol) was added. Thereaction mixture was allowed to warm to r.t. and stirred for a further60 h. The reaction mixture was poured into ice water, and the resultingmixture was filtered. The collected precipitate was dried under vacuumto give racemic tert-butyl trans-(3-carbamoylcyclohexyl)carbamate (0.95g, 61%). ¹H NMR (400 MHz, CDCl₃, 30° C.) 1.45 (9H, s), 1.48-1.56 (2H,m), 1.62-1.78 (4H, m), 1.79-1.92 (2H, m), 2.45 (1H, dt), 3.84 (1H, s),4.57 (1H, s), 5.35 (1H, br s), 5.66 (1H, br s).

Preparation of racemic tert-butyl(trans-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate

Tetrakis(triphenylphosphine)palladium(0) (0.094 g, 0.08 mmol) was addedto racemic tert-butyl (trans-3-carbamoylcyclohexyl)carbamate (0.235 g,0.97 mmol),3-(2-chloro-5-fluoropyridin-4-yl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(0.215 g, 0.81 mmol, prepared according to Example 25),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (0.094 g, 0.16mmol) and cesium carbonate (0.791 g, 2.43 mmol) in 1,4-dioxane (6 mL)and water (1.2 mL). The resulting suspension was degassed for 10 minutesunder nitrogen and then stirred at 100° C. for 48 h. The mixture wascooled, diluted with water (40 mL), and extracted with EtOAc (3×20 mL).The combined organics were evaporated to crude material. The crudeproduct was purified by flash silica chromatography, elution gradient 0to 60% ethyl acetate in heptane. Pure fractions were evaporated todryness to afford racemic tert-butyl(trans-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.322 g, 84%) as a white foam solid. m/z: ES+ [M+H]+ 472.

Preparation of racemictrans-3-amino-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide

Trifluoroacetic acid (2.3 g, 20 mmol) was added to a solution of racemictert-butyl(trans-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate(0.322 g, 0.68 mmol) in DCM (10 mL). After 15 min, the reaction waspurified by ion exchange chromatography using an SCX column. The desiredproduct was eluted from the column using 1M NH₃ in MeOH and purefractions were concentrated under reduced pressure to afford racemictrans-3-amino-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide(0.237 g, 93%) as a white dry film. m/z: ES+ [M+H]+ 372.

Example 85: Preparation of(1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexane-1-carboxamide

5-Chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-amine(56.7 g, 215.7 mmol) and pyridine (0.073 L, 863 mmol) were added to afine suspension of (1S,3R)-3-acetamidocyclohexane-1-carboxylic acid(49.9 g, 84% w/w, 227 mmol) in EtOAc (1 L) under a nitrogen atmosphere.Then 1-propanephosphonic anhydride (T₃P, ≥50 wt % in EtOAc; 206 g, 324mmol) was added slowly over 1 hour. After an additional 20 h ofstirring, water (400 mL) was added, and the biphasic mixture was stirredfor an additional 10 minutes. The organic layer was washed withsaturated aqueous sodium carbonate (300 mL) and water (300 mL). Theorganic layer was concentrated under reduced pressure, and the resultingsolid was taken up in acetonitrile (300 mL) and reconcentrated underreduced pressure. Acetonitrile (450 mL) was again added, and theresulting suspension was heated to 70° C. Seed crystals were added, andthe thick suspension was stirred at 50° C. for 3 h. The mixture was thencooled to 20° C. and maintained under these conditions for 3 days. Thesuspension was filtered, and the isolated precipitate was washed withacetonitrile (3×100 mL) and then dried under reduced pressure at 45° C.This yielded(1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexane-1-carboxamideas an off-white crystalline solid (83.2 g, 90%). ¹H NMR (400 MHz, CDCl₃,23° C.) 1.08-1.23 (1H, m), 1.33 (6H, s), 1.37-1.57 (3H, m), 1.86-2.04(6H, m), 2.26 (1H, d), 2.38-2.52 (1H, m), 2.95 (2H, s), 3.79-3.92 (1H,m), 3.94 (2H, s), 5.51 (1H, d), 8.09 (1H, s), 8.12 (1H, s), 8.22 (1H,s), 8.24 (1H, s). m/z: ES+ [M+H]+ 430. Characterisation consistent withExample 14.

The crystals obtained from Example 85 were analyzed by XRPD, confirmingthat the solid contains exclusively Form A, previously characterized inExample 14.

Procedures used to prepare the starting materials5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-amineand (1S,3R)-3-acetamidocyclohexane-1-carboxylic acid are describedbelow:

Preparation of cis-3-(isopropoxycarbonyl)cyclohexanaminium chloride

Hydrochloric acid (5 to 6 M in 2-propanol; 16 mL) was added to asuspension of 3-aminobenzoic acid (10 g, 73 mmol) in 2-propanol (100mL). Then rhodium (5% on Al₂O₃; 0.75 g, 0.36 mmol) was added, and themixture was subjected to a hydrogen atmosphere (8 bar) at 100° C. for 3days. Additional hydrochloric acid (5 to 6 M in 2-propanol; 5 mL) wasadded, and the mixture was stirred at 70° C. in a sealed steel vesselfor an additional 2 days. The mixture was then filtered through Celite®using 2-propanol (2×10 mL) and water (2×20 mL) washes. The filtrate wasconcentrated under reduced pressure to afford a white solid. This solidwas treated with 2-propanol (50 mL) and reconcentrated under reducedpressure before being suspended in 100 mL of hot (70° C.) isopropylacetate. The mixture was slowly cooled to 20° C. and then stirred for anadditional 15 minutes. The mixture was filtered, and the solid collectedwas washed with isopropyl acetate (3×30 mL) and dried under reducedpressure to afford cis-3-(isopropoxycarbonyl)cyclohexanaminium chloride(7.5 g, 46%) as a white solid. ¹H NMR (400 MHz, D₂O, 23° C.) 1.27 (6H,d), 1.30-1.57 (4H, m), 1.90-2.14 (3H, m), 2.28 (1H, d), 2.52 (1H, tt),3.20-3.36 (1H, m), 5.01 (1H, hept).

Preparation of cis-isopropyl 3-aminocyclohexanecarboxylate

A solution of sodium hydroxide (2.72 g, 68.1 mmol) in water (20 mL) wasslowly added to a mixture of cis-3-(isopropoxycarbonyl)cyclohexanaminiumchloride (14.0 g, 62 mmol) in water (50 mL) and i-Pr acetate (150 mL) at20° C. until a pH of 10.9 was obtained. The aqueous layer was extractedwith i-Pr acetate (2×50 mL) and the pooled organic layer wasconcentrated under reduced pressure. The resulting residue wasreconcentrated from isopropyl acetate (2×20 mL) to afford cis-isopropyl3-aminocyclohexanecarboxylate as a colorless non-viscous oil (11.86 g,100% yield). ¹H NMR (400 MHz, CDCl₃, 20° C.) 0.83-0.97 (1H, m),0.82-1.27 (5H, m), 1.11 (6H, d), 1.67-1.82 (3H, m), 1.93-2.02 (1H, m),2.18 (1H, tt), 2.56 (1H, tt), 4.88 (1H, hept).

Preparation of (1S,3R)-isopropyl 3-acetamidocyclohexanecarboxylate

NOVOZYM 435 (3 g, purchased from Novozymes A/S Denmark (activity 10000PLU/g)) was added to a clear solution of cis-isopropyl3-aminocyclohexanecarboxylate (59.4 g, 298 mmol) in isopropyl acetate(480 mL). The mixture was stirred at 20° C. for 12 h and then filtered.The collected precipitate was washed with isopropyl acetate (150 mL),and the filtrate was washed with aqueous hydrochloric acid (2 M; 200mL). The aqueous layer was extracted with isopropyl acetate (3×150 mL),and the combined organic layers were again filtered and concentratedunder reduced pressure to a white solid (43 g). This solid was taken upin isopropyl acetate (2×200 mL) and reconcentrated under reducedpressure. The resulting residue was dissolved in isopropyl acetate (400mL) and washed with saturated aqueous sodium carbonate (50 mL). Theaqueous layer was extracted with isopropyl acetate (100 mL), and thecombined organic layers were washed with water (50 mL) and concentratedunder reduced pressure to a white solid. This solid was taken up inisopropyl acetate (2×100 mL) and again reconcentrated under reducedpressure. The resulting residue was treated with cyclopentylmethylether(70 mL) and cyclohexane (140 mL). This afforded a suspension, which washeated to 70° C. A homogenous solution was obtained, which, upon coolingto 20° C., became a mixture. Seed crystals were added at 50° C. Theresulting suspension was stirred for 2 days followed by filtration andwashing of the solid with 33% cyclopentylmethyl ether in cyclohexane(2×30 mL). After drying under reduced pressure, (1S,3R)-isopropyl3-acetamidocyclohexanecarboxylate (26.8 g, 40%) was obtained as a whitesolid. ¹H NMR (400 MHz, CDCl₃, 20° C.) 1.01-1.13 (1H, m), 1.20 (6H, d),1.22-1.45 (3H, m), 1.77-1.93 (3H, m), 1.94 (3H, s), 2.12-2.26 (1H, m),2.37 (1H, tt), 3.70-3.91 (1H, m), 4.96 (1H, p), 5.67 (1H, d).

Analytical SFC Conditions:

Column: Lux C2

Column Dimensions: 3 μm, 4.6 mm diameter, 150 mm length,

Column Temperature: 40° C.

Mobile Phase A: CO₂ (100%)

Mobile Phase B: Isopropanol

Gradient: Isocratic 15% Mobile Phase B

Outlet Pressure: 120 bar

Flow Rate: 3.5 mL/min over 5 min

Retention Time:

1.9 min, (1R,3S)-isopropyl 3-acetamidocyclohexanecarboxylate

2.7 min, (1S,3R)-isopropyl 3-acetamidocyclohexanecarboxylate

e.e.

99.9%, (1S,3R)-isopropyl 3-acetamidocyclohexanecarboxylate

Preparation of (1S,3R)-3-acetamidocyclohexanecarboxylic acid

A solution of aqueous sodium hydroxide (3.8 M; 3.9 mL, 14.8 mmol) wasadded under an atmosphere of nitrogen to a solution of (1S,3R)-isopropyl3-acetamidocyclohexanecarboxylate (1.71 g, 7.37 mmol) in MeOH (3 mL).The mixture was stirred at 20° C. for 1 hour and then a solution ofaqueous hydrochloric acid (3.8 M; 4.5 mL) was added to the mixture untila pH of 1 was achieved. Ethyl acetate (10 mL) was added, and the layerswere separated. The aqueous layer was extracted with ethyl acetate (4×10mL). The combined organic layers were concentrated under reducedpressure at 40° C. The resulting residue was reconcentrated from ethylacetate (2×10 mL) to afford (1S,3R)-3-acetamidocyclohexanecarboxylicacid (1.4 g, 94%; 92 wt %) contaminated with sodium chloride as a whitesolid. ¹H NMR (400 MHz, CD₃OD, 20° C.) 1.08-1.47 (4H, m), 1.78-1.99 (6H,m), 2.12 (1H, d), 2.3-2.45 (1H, m), 3.58-3.74 (1H, m). m/z: ES+ [M+H]+186.

3-Bromo-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

A reactor was charged with5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (79.5 g, 525 mmol;prepared according to Example 14) and CH₂Cl₂ (800 mL) under a nitrogenatmosphere. NBS (95.4 g, 533 mmol) was added portionwise over 15minutes. The reaction temperature was kept between 20 and 23° C. duringaddition. After 0.5 h of stirring at 20° C., a solution of aqueous 8 wt% Na₂SO₃ (250 mL) was added, and the biphasic mixture was stirred underthese conditions for 45 minutes. The organic layer was washed withsaturated aqueous sodium carbonate (1×250 mL, 1×200 mL) and water (100mL). The organic layer was then concentrated under reduced pressure at30° C. and 400 mbar. The resulting residue was reconcentrated from THF(3×100 mL) to afford3-bromo-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (138 g, 99%;81 wt % by NMR strength analysis) as a pale brown oil. This material wasused in the next step without further purification. ¹H NMR (400 MHz,CDCl₃, 20° C.) 1.29 (6H, s), 2.64 (2H, s), 3.89 (2H, s), 7.41 (1H, s).

Preparation of5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

A solution of butyllithium (2.5 M in hexanes; 0.309 L, 774 mmol) wasslowly added to a solution of3-bromo-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (137 g, 516mmol; 81 wt %) and triisopropyl borate (0.21 L, 929 mmol) in THF (0.7 L)and toluene (0.7 L) at −70° C. under a nitrogen atmosphere in a 3 L3-necked flask equipped with a thermometer. The reaction temperature waskept between −65 to −70° C. during addition. After addition was completea solution of 2,3-dimethylbutane-2,3-diol (91 g, 774 mmol) in toluene(0.5 L) was added over 10 minutes. The mixture was slowly allowed toattain r.t. in the ice-bath and was then stirred for an additional 18 h.The reaction mixture was transferred to a 5 L reactor containing a cold10° C. solution of saturated aqueous ammonium chloride (2.5 L). Thebiphasic mixture was stirred for 15 minutes at 20° C., and the organiclayer was washed with water (2×500 mL) followed by concentration at 35°C. to afford5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoleas a light yellow solid (194 g, 92%; 64 wt % by NMR strength analysis).This material was used in the next step without further purification. ¹HNMR (400 MHz, CDCl₃, 20° C.) 1.21 (6H, s), 1.26 (12H, s), 2.77 (2H, s),3.84 (2H, s), 7.74 (1H, s). m/z: ES+ [M+H]+ 263.

Preparation of 5-chloro-4-iodopyridin-2-amine

5-Chloro-2-fluoro-4-iodopyridine (90 g, 350 mmol) dissolved in NMP (200mL) was added to a 10° C. solution of concentration aqueous ammoniumhydroxide (aq. 26%; 298 g, 4.54 mol). The reaction temperature was keptbelow 10° C. during addition. The vessel was sealed and then warmed to100° C. After 18 h, the mixture was cooled to r.t., after which asuspension was obtained. The crude mixture was combined with thatobtained in a small scale experiment carried out under identicalconditions starting from 8 g (31 mmol) of5-chloro-2-fluoro-4-iodopyridine. MTBE (500 mL) and water (200 mL) wereadded. The layers were separated, and the aqueous layer was extractedwith MTBE (2×250 mL). The combined organic layers were washed with water(100 mL) and then concentrated under reduced pressure to a beige solid.This solid was reconcentrated under reduced pressure from MTBE (2×200mL) to remove residual water. Then the crude mixture was dissolved inhot (65° C.) toluene (400 mL) using a rotary evaporator. The mixture wasthen slowly allowed to attain 45° C. after which seed crystals wereadded. The suspension obtained was slowly allowed to cool to 10° C. andwas then stirred for an additional 18 h under these conditions. Thesuspension was filtered and the solid collected was washed with ice-coldtoluene (2×70 mL). This yielded 5-chloro-4-iodopyridin-2-amine (63.8 g,65.9%) as a colorless solid. ¹H NMR (400 MHz, DMSO-d₆, 20° C.) 6.23 (2H,s), 7.04 (1H, s), 7.92 (1H, s).

Preparation of5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-amine

Potassium carbonate (81 g, 582.6 mmol) and Pd(dppf)C12 (3.41 g, 4.66mmol) were added sequentially to a degassed mixture of5-chloro-4-iodopyridin-2-amine (59.9 g, 233 mmol) and5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(64 wt %; 110 g, 268 mmol) in acetonitrile (500 mL) and water (500 mL).The clear pale red biphasic mixture was heated to 50° C. After vigorousstirring for 2 h, additional Pd(dppf)C12 (1.0 g, 1.4 mmol) was added,and the mixture was stirred for an additional 20 h under theseconditions. The mixture was then cooled to 20° C. and ethyl acetate (450mL) was added. The layers were separated, and the organic layer waswashed with water (200 mL) The Pd-scavenger Silicycle (SilaMetS)-thiol,(cat # R51030B; 20 g) was then added to the organic layer, and themixture was further stirred for 2 h at 20° C. The mixture was thenfiltered and concentrated under reduced pressure to a brown solid. Thissolid was dissolved in DCM (100 mL), and the solution was then filteredthrough a short pad of silica gel, eluting with 5% 2-propanol in CH₂Cl₂.Product fractions were concentrated under reduced pressure to give abrown solid. Methylisobutylketone (MIBK, 250 mL) was added, and theresulting suspension was heated to 70° C. and then slowly cooled to 20°C. The resulting suspension was stirred under these conditions for 18 hand then filtered washed with methyl isobuylketone (5×30 mL) to afford5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-amineas a faint pink solid (50.7 g, 193 mmol). ¹H NMR (400 MHz, CDCl₃, 20°C.) 1.28 (6H, s), 2.81 (2H, s), 3.91 (2H, s), 4.56 (2H, br s), 6.41 (1H,s), 7.83 (1H, s), 8.03 (1H, s). m/z: ES+ [M+H]+ 263.

Example 86: Preparation of(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide

4-(5,5-Dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-amine(31.8 g, 129 mmol) and pyridine (43.9 mL, 517 mmol) were added under anatmosphere of nitrogen at 20° C. to a suspension of(1S,3R)-3-acetamidocyclohexane-1-carboxylic acid (29.9 g, 136 mmol; 84wt %, prepared according to Example 85) in EtOAc (800 mL). T₃P (≥50 wt %in EtOAc; 123 g, 194 mmol) was added over 40 minutes, and the resultingmixture was stirred for 21 h under these conditions. Then water (400 mL)was added. The biphasic mixture was stirred for 10 minutes, and thelayers were separated. The organic layer was washed with saturatedaqueous sodium carbonate (300 mL) and water (300 mL) before beingfiltered and concentration under reduced pressure to afford a dark brownsemi-solid. Acetonitrile (250 mL) was added, and the mixture was warmedto 70° C. after which a homogenous brown solution was obtained. Themixture was allowed to attain 60° C., additional acetonitrile (200 mL)was added, and the slurry was stirred for an additional 2 h under theseconditions before being allowed to slowly cool to 20° C. The suspensionobtained was stirred for 3 days followed by filtration and washing ofthe solid with CH₃CN (250 mL). After drying under reduced pressure at48° C. for 20 h,(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide(49.2 g, 119 mmol) was obtained as an off-white crystalline solid. ¹HNMR (400 MHz, CDCl₃, 20° C.) 1.08-1.23 (1H, m), 1.33 (6H, s), 1.37-1.58(3H, m), 1.88-1.94 (1H, m), 1.96-2.01 (5H, m), 2.26 (1H, d), 2.38-2.42(1H, m), 3.00 (2H, s), 3.80-3.91 (1H, m), 3.93 (2H, s), 5.47 (1H, d),8.00 (1H, d), 8.09-8.17 (2H, m), 8.31 (1H, d). m/z: ES+ [M+H]+ 414.Consistent with characterisation in Example 25

The crystals of(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamideobtained by the procedure described in Example 86 were analyzed by XRPD.The results are tabulated below and are shown in FIG. 5, confirming thatthe solid contains exclusively Form B.

(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide,Form B main peaks are shown in Table 3 below:

Peak 2θ Intensity % 1 8.3 100.0 (vs)  2 11.0 12.6 (s) 3 13.1 13.5 (s) 416.6 51.0 (vs) 5 19.4 42.7 (vs) 6 20.4 11.7 (s) 7 22.3 68.0 (vs) 8 27.017.1 (s) 9 27.2 22.0 (s) 10 28.6 32.1 (vs)

According to the present invention there is provided a crystalline form,Form B, which has an X-ray powder diffraction pattern with specificpeaks at about 2-theta=8.3, 11.0, 13.1, 16.6, 19.4, 20.4, 22.3, 27.0,27.2 and 28.6°. DSC analysis indicated the Form B melts with an onsetpoint at 191° C. and a peak at 193° C. TGA indicated that Form Bexhibits a mass loss of about 1.6% upon heating from 22° C. to 210° C. Arepresentative DSC/TGA thermogram is shown in FIG. 6.

Conversion of Form A to Form B

100 mg of(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide,Form A (isolated from Example 25) was added in a 20 mL vial. To thevial, 2.0 mL of acetone was added to obtain a suspension. The resultingslurry was stirred at ambient temperature over the weekend and was thendried in air by evaporation. The resulting white solid obtained wascharacterized and identified as(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide,Form B.

Procedures used to prepare the starting material4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-amineare described below:

Preparation of 5-fluoro-4-iodopyridin-2-amine

A 5 L steel hydrogenation vessel was charged with aqueous ammonia (26%;777 g, 11.9 mol) and 2,5-difluoro-4-iodopyridine (220 g, 913 mmol). Themixture was cooled to 5° C., and NMP (500 mL) was added slowly overminutes (gas evolution). The vessel was sealed and the reaction mixturewas then heated to 100° C. After 36 h, the reaction temperature wasdecreased to 90° C., and the reaction was maintained under theseconditions for 3.5 days. The mixture was then cooled to 5° C., and MTBE(1 L) and water (500 mL) were added. The aqueous layer was extractedwith MTBE (2×500 mL), and the combined organic layers were washed withwater (200 mL), filtered, and concentrated under reduced pressure. Theresulting pale yellow solid was reconcentrated from MTBE (2×500 mL), andthen toluene (400 mL) was added. The resulting mixture was heated to 70°C., and a homogenous brown solution was obtained. Heptane (500 mL) wasslowly added. The homogenous solution was then slowly allowed to reach18° C. in a water bath with seed crystals added once the mixtureachieved 42° C. The mixture was stirred overnight under theseconditions. The suspension was filtered, and the solid collected waswashed with 45% toluene in heptane (200 mL) followed by drying underreduced pressure at 40° C. to afford 5-fluoro-4-iodopyridin-2-amine (111g, 51%) as a pale grey solid. ¹H NMR (400 MHz, CDCl₃, 20° C.) 4.52 (2H,br s), 6.89 (1H, d), 7.79 (1H, s).

Preparation of4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-amine

Potassium carbonate (63.1 g, 457 mmol) and Pd(dppf)C12 (2.67 g, 3.66mmol) were added sequentially under nitrogen to a degassed mixture of5-fluoro-4-iodopyridin-2-amine (43.5 g, 182.8 mmol) and5,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(86 g, 210 mmol; 64 wt %, prepared according to Example 85) inacetonitrile (400 mL) and water (400 mL). The pale red biphasic mixturewas heated to 50° C. and vigorously stirred for 5 h. The reaction wascooled and then ethyl acetate (400 mL) was added. The layers wereseparated, and the organic layer was washed with water (200 mL). ThePd-scavenger Silicycle (SilaMetS)-thiol, (cat # R51030B, 10 g) was addedto the organic layer, and the mixture was then stirred over night at 20°C. The mixture was filtered, and the filtrate was concentrated underreduced pressure to afford a brown solid. Isopropanol (200 mL) wasadded, and the mixture was heated to 70° C. which gave a homogenous darkbrown solution. The mixture was then slowly allowed to cool to 20° C.and then stirred for 15 h. The suspension obtained was filtered and thesolid collected was washed with cold (4° C.) isopropanol (3×30 mL) toafford4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-amine(32 g, 71%) as a pale brown solid. ¹H NMR (400 MHz, CDCl₃, 20° C.) 1.34(6H, s), 2.91 (2H, s), 3.95 (2H, s), 4.30 (2H, s), 6.51 (1H, d), 7.89(1H, s), 7.93 (1H, d). m/z: ES+ [M+H]+ 247.

All references cited herein, including patents, patent applications,papers, text books, and the like, and the references cited therein, tothe extent that they are not already, are hereby incorporated herein byreference in their entirety for all purposes.

What is claimed is:
 1. A method of treating a hematological malignancy,comprising: administering to a subject suffering from a hematologicalmalignancy an effective amount of a compound selected from:(R)—N-(5-chloro-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)piperidine-3-carboxamide;(1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;Cis-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide;(R)—N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)piperidine-3-carboxamide;cis-3-hydroxy-N-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclobutanecarboxamide;(1S,3R)-3-acetamido-N-(5-chloro-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1R,3S)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(5-chloro-4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(5-chloro-4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrlo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1S,3R)—N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide;N-((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide;N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide;(1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-((S)-2-hydroxypropanamido)cyclohexanecarboxamide;(1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(R)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide;(S)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide;(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide;cis-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrol-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide;cis-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide;(1S,3R)-3-acetamido-N-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)cyclohexanecarboxamide;trans-3-hydroxy-N-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)cyclobutanecarboxamide;(1S,3R)-3-acetamido-N-(6-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrimidin-4-yl)cyclohexanecarboxamide;(1S,3R)—N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(2-cyanoacetamido)cyclohexanecarboxamide;tert-butyl((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate;(1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1S,3R)—N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide;(R)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide;N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)-3-methyloxetane-3-carboxamide;(S)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide;(R)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide;(1S,3R)—N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)-3-((S)-2-hydroxypropanamido)cyclohexanecarboxamide;(S)—N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-3-carboxamide;(1S,3R)-3-acetamido-N-(5-cyano-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;Isomer 1 of(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;Isomer 2 of(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1R,3S)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(S)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide;(R)—N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)tetrahydrofuran-2-carboxamide;(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-methylpyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclopentanecarboxamide;(1S,3R)-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-amino-N-(4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide;(1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(3-hydroxypropanamido)cyclohexanecarboxamide;(1S,3R)—N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)-3-(cis-3-hydroxycyclobutanecarboxamido)cyclohexanecarboxamide(1S,3R)-3-amino-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide;(1S,3R)—N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide;(1S,3R)—N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-3-(1-hydroxycyclopropanecarboxamido)cyclohexanecarboxamide;N-((1R,3S)-3-((5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide;cis-N-(5-chloro-4-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)pyridin-2-yl)-3-hydroxycyclobutanecarboxamide;Isomer 1 oftrans-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;Isomer 2 oftrans-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;Isomer 1 oftrans-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;Isomer 2 oftrans-3-acetamido-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(5-fluoro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;Isomer 1 of(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;Isomer 2 of(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(5-chloro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide;Isomer 1 of(1S,3R)-3-acetamido-N-(5-chloro-4-(6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;Isomer 2 of(1S,3R)-3-acetamido-N-(5-chloro-4-(6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;Isomer 1 of(1S,3R)-3-acetamido-N-(5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;Isomer 2 of(1S,3R)-3-acetamido-N-(5-chloro-4-(6-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;Isomer 1 of(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;Isomer 2 of(1S,3R)-3-acetamido-N-(5-chloro-4-(5-methoxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(5-fluoro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1S,3R)—N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-methylpyridin-2-yl)-3-(2-hydroxyacetamido)cyclohexanecarboxamide;N-((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide;(1S,3R)-3-acetamido-N-(5-methyl-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(5-chloro-4-(7-hydroxy-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(5-chloro-4-(5-(4-hydroxybutyl)-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexanecarboxamide;Isomer 1 of(1S,3R)-3-acetamido-N-(5-chloro-4-(4-hydroxy-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;Isomer 2 of(1S,3R)-3-acetamido-N-(5-chloro-4-(4-hydroxy-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide;(1R,3S)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexanecarboxamide;(1S,3R)-3-acetamido-N-(5-chloro-4-(5-(3-hydroxy-2,2-dimethylpropyl)-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1-carboxamide;(1S,3R)-3-acetamido-N-(5-chloro-4-(6-hydroxy-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexane-1-carboxamide;(1R,3R)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide;and(1S,3S)-3-acetamido-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)cyclohexane-1-carboxamide,or a pharmaceutically acceptable salt thereof.
 2. A method of treating ahematological malignancy, comprising: administering to a subjectsuffering from a hematological malignancy an effective amount of(1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide,or a pharmaceutically acceptable salt thereof.
 3. The method of claim 2,comprising: administering to a subject suffering from a hematologicalmalignancy an effective amount of(1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide.4. The method of claim 2, comprising: administering to a subjectsuffering from a hematological malignancy an effective amount of apharmaceutically acceptable salt of(1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide.5. The method of claim 3, wherein the hematological malignancy is acutemyeloid leukemia, multiple myeloma, chronic lymphocytic leukemia,diffuse large B cell lymphoma, Burkitt's lymphoma, or follicularlymphoma.
 6. The method of claim 3, wherein the hematological malignancyis acute myeloid leukemia.